U.S. patent application number 10/617498 was filed with the patent office on 2004-08-05 for heterocyclically substituted benzoylureas, process for their preparation and their use as pharmaceuticals.
This patent application is currently assigned to Aventis Pharma Deutschland GmbH. Invention is credited to Burger, Hans-Joerg, Defossa, Elisabeth, Herling, Andreas, Kadereit, Dieter, Klabunde, Thomas, Roedern, Erich Von, Schoenafinger, Karl, Wendt, Karl-Ulrich.
Application Number | 20040152743 10/617498 |
Document ID | / |
Family ID | 30118721 |
Filed Date | 2004-08-05 |
United States Patent
Application |
20040152743 |
Kind Code |
A1 |
Schoenafinger, Karl ; et
al. |
August 5, 2004 |
Heterocyclically substituted benzoylureas, process for their
preparation and their use as pharmaceuticals
Abstract
The invention relates to heterocyclically substituted
benzoylureas and also to their physiologically tolerated salts and
physiologically functional derivatives. Compounds are described of
the formula I 1 where the radicals are defined as specified, and
also their pharmaceutically acceptable salts and processes for
their preparation. The compounds are suitable, for example, for
treating type 2 diabetes.
Inventors: |
Schoenafinger, Karl;
(Alzenau, DE) ; Defossa, Elisabeth; (Idstein,
DE) ; Kadereit, Dieter; (Kelkheim, DE) ;
Roedern, Erich Von; (Hattersheim, DE) ; Klabunde,
Thomas; (Frankfurt, DE) ; Burger, Hans-Joerg;
(Morristown, NJ) ; Herling, Andreas; (Bad Camberg,
DE) ; Wendt, Karl-Ulrich; (Frankfurt, DE) |
Correspondence
Address: |
ROSS J. OEHLER
AVENTIS PHARMACEUTICALS INC.
ROUTE 202-206
MAIL CODE: D303A
BRIDGEWATER
NJ
08807
US
|
Assignee: |
Aventis Pharma Deutschland
GmbH
Frankfurt
DE
|
Family ID: |
30118721 |
Appl. No.: |
10/617498 |
Filed: |
July 11, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60430782 |
Dec 4, 2002 |
|
|
|
Current U.S.
Class: |
514/357 ;
514/408; 514/522; 514/563; 514/594; 558/403; 562/439; 564/44 |
Current CPC
Class: |
C07D 307/68 20130101;
A61P 9/10 20180101; A61P 3/08 20180101; C07D 235/18 20130101; C07D
231/26 20130101; C07D 257/04 20130101; C07D 211/60 20130101; C07D
271/113 20130101; A61P 3/10 20180101; C07D 233/56 20130101; C07D
249/12 20130101; C07D 271/10 20130101; C07D 249/08 20130101; A61P
3/00 20180101; C07D 231/12 20130101; A61P 43/00 20180101; C07D
253/07 20130101; C07D 211/62 20130101; A61P 5/50 20180101; A61P
3/06 20180101 |
Class at
Publication: |
514/357 ;
514/522; 514/563; 514/594; 558/403; 562/439; 564/044; 514/408 |
International
Class: |
A61K 031/44; A61K
031/40 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 12, 2002 |
DE |
10231627.9 |
Feb 17, 2003 |
DE |
10306503.2 |
May 6, 2003 |
DE |
10320326.5 |
Claims
We claim:
1. A compound of the formula 1, 13wherein R1 and R2 are each
independently H, O--(C.sub.1-C.sub.6)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, COO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl or
(C.sub.1-C.sub.6)-alkyl, wherein said (C.sub.1-C.sub.6)-alkyl is
optionally substituted by OH, O--(C.sub.1-C.sub.4)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.4)-alkyl or N[(C.sub.1-C.sub.6)-alkyl].sub.2; R3
and R4 are each independently F, Cl, Br, OH, NO.sub.2, CN,
(C.sub.1-C.sub.6)-alkyl, 0-(C.sub.1-C.sub.4)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl or (C.sub.2-C.sub.6)-alkynyl, wherein
said (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.4)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl and (C.sub.2-C.sub.6)-alkynyl are
optionally mono- or polysubstituted by F, Cl or Br; R5 is H, F, Cl,
Br, OH, NO.sub.2, CN, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.4)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl or
(C.sub.2-C.sub.6)-alkynyl, wherein said (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.4)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1- -C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl and
(C.sub.2-C.sub.6)-alkynyl are optionally mono- or polysubstituted
by F, Cl or Br; A is H, F, Cl, Br, OH, NO.sub.2, CN,
(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-COO(C.sub.1-C- .sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkeny- l,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
S(O).sub.1-2-(C.sub.1-C.sub.6)-alkyl-, NH--(C.sub.1-C.sub.6)-alkyl,
N-[(C.sub.1-C.sub.6)-alkyl].sub.2, COOH,
COO--(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH--(C.sub.1-C.sub.6)-alkyl, CON-[(C.sub.1-C.sub.6)-alkyl].-
sub.2, SO.sub.2NH.sub.2, SO.sub.2NH--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N-[(C.sub.1-C.sub.6)-alkyl].sub.2 or NHCOR6, wherein said
(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-COO(C.sub.1-C- .sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkeny- l,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
S(O).sub.1-2--(C.sub.1-C.sub.6)-alkyl-,
NH--(C.sub.1-C.sub.6)-alkyl, N-[(C.sub.1-C.sub.6)-alkyl].sub.2,
COO--(C.sub.1-C.sub.6)-alkyl, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
SO.sub.2NH--(C.sub.1-C.sub.6)-alkyl and
SO.sub.2N-[(C.sub.1-C.sub.6)-alky- l].sub.2 are optionally mono- or
polysubstituted by F, Cl, Br, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, CONH--(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6)-alkyl]2 or OCO--(C.sub.1-C.sub.6)-alkyl; R6
is H, (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkylene,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-CO--(C.sub.1-C.sub.6)-alkyl,
(Co-C.sub.6)-alkylene-COOH, (C.sub.1-C.sub.6)-alkylene-CONH.sub.2,
(C.sub.6-C.sub.10)-aryl,
(C.sub.1-C.sub.4)-alkylene-(C.sub.6-C.sub.10)-ar- yl, heteroaryl,
(C.sub.1-C.sub.4)-alkylene-heteroaryl or CO-heteroaryl, wherein
said (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkylene,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH and
(C.sub.1-C.sub.6)-alkylene-CONH.sub.2 are optionally mono- or
polysubstituted by F, Cl, Br, O(C.sub.1-C.sub.4-alkyl),
COO--(C.sub.1-C.sub.4-alkyl) or N-[(C.sub.1-C.sub.4)-alkyl].sub.2
and said (C.sub.6-C.sub.10)-aryl,
(C.sub.1-C.sub.4)-alkylene-(C.sub.6-C.sub.10)-aryl, heteroaryl,
(C.sub.1-C.sub.4)-alkylene-heteroaryl and CO-heteroaryl are
optionally mono- or polysubstituted by F, Cl, Br, NO.sub.2, CN,
O--(C.sub.1-C.sub.4-alkyl), S--COO(C.sub.1-C.sub.4-alkyl),
COO--(C.sub.1-C.sub.4-alkyl), N-[(C.sub.1-C.sub.4)-alkyl].sub.2 or
(C.sub.1-C.sub.6)-alkyl; n is 0, 1, 2 or 3; m is 1, 2, 3, 4 or 5; o
is 0, 1, 2 or 3; Het is a heterocyclic 4- to 7-membered ring which
may contain up to four N, O or S heteroatoms and wherein said
heterocyclic 4- to 7-membered ring is optionally substituted by R7,
R8 and R9, with the proviso that said heterocyclic 4- to 7-membered
ring cannot be pyrrole; and R7, R8, and R9 are each independently
H, F, Cl, Br, (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl, O--(C.sub.2-C.sub.6)-alkynyl, OH,
oxo, O--(C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N-[(C.sub.1-C.sub.6)-alkyl].sub.2,
COOH, CO--(C.sub.1-C.sub.6)-alkyl, COO--(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.0-C.sub.6)-alkylene-aryl or
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl, wherein
said (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl, O--(C.sub.2-C.sub.6)-alkynyl,
0-(C.sub.1-C.sub.6)-alkyl, NH--(C.sub.1-C.sub.6)-alkyl,
N-[(C.sub.1-C.sub.6)-alkyl].sub.2, CO--(C.sub.1-C.sub.6)-alkyl,
COO--(C.sub.1-C.sub.6)-alkyl, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.0-C.sub.6)-alkylene-aryl and
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl are
optionally substituted by COOH, CONH.sub.2,
CONH--(C.sub.1-C.sub.6)-alkyl, CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
OCO--(C.sub.1-C.sub.6)-alkyl, F, Cl, (C.sub.1-C.sub.6)-alkyl or
O--(C.sub.1-C.sub.6)-alkyl; and two radicals selected from said R7,
R8 and R9 may optionally be bonded together to form a ring fused
onto said heterocyclic 4- to 7-membered ring; and pharmaceutically
acceptable salts thereof.
2. The compound of claim 1 wherein R1 and R2 are H; R3 and R4 are
each independently F, Cl or Br; R5 is H, F, Cl, Br, OH, NO.sub.2,
CN, (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.4)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, (C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl or
(C.sub.2-C.sub.6)-alkynyl, wherein said (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.4)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1- -C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, 0-(C.sub.2-C.sub.6)-alkenyl and
(C.sub.2-C.sub.6)-alkynyl are optionally mono- or polysubstituted
by F, Cl or Br; A is H, F, Cl, Br, OH, NO.sub.2, CN,
(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-COO(C.sub.1-C- .sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkeny- l,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
S(O).sub.1-2--(C.sub.1-C.sub.6)-alkyl-,
NH--(C.sub.1-C.sub.6)-alkyl, N-[(C.sub.1-C.sub.6)-alkyl].sub.2,
COOH, COO--(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH--(C.sub.1-C.sub.6)-alkyl, CON-[(C.sub.1-C.sub.6)-alkyl].-
sub.2, SO.sub.2NH.sub.2, SO.sub.2NH--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N-[(C.sub.1-C.sub.6)-alkyl].sub.2 or NHCOR6, wherein said
(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-COO(C.sub.1-C- .sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkeny- l,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
S(O).sub.1-2--(C.sub.1-C.sub.6)-alkyl-,
NH--(C.sub.1-C.sub.6)-alkyl, N-[(C.sub.1-C.sub.6)-alkyl].sub.2,
COO--(C.sub.1-C.sub.6)-alkyl, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
SO.sub.2NH--(C.sub.1-C.sub.6)-alkyl and
SO.sub.2N-[(C.sub.1-C.sub.6)-alky- l].sub.2 are optionally mono- or
polysubstituted by F, Cl, Br, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2 or
OCO--(C.sub.1-C.sub.6)-alkyl; R6 is H, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkylene,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-CONH.sub.2, (C.sub.6-C.sub.10)-aryl,
(C.sub.1-C.sub.4)-alkylene-(C.sub.6-C.sub.10)-ar- yl, heteroaryl,
(C.sub.1-C.sub.4)-alkylene-heteroaryl or CO-heteroaryl, wherein
said (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.3-C.sub.7)-- cycloalkyl-(C.sub.1-C.sub.4)-alkylene,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH and
(C.sub.1-C.sub.6)-alkylene-CONH.sub.2 are optionally mono- or
polysubstituted by F, Cl, Br, O--(C.sub.1-C.sub.4)-alkyl,
COO--(C.sub.1-C.sub.4-alkyl), or N-[(C.sub.1-C.sub.4)-alkyl].sub.2,
and said (C.sub.6-C.sub.10)-aryl,
(C.sub.1-C.sub.4)-alkylene-(C.sub.6-C.sub.10)-aryl, heteroaryl,
(C.sub.1-C.sub.4)-alkylene-heteroaryl and CO-heteroaryl are
optionally mono- or polysubstituted by F, Cl, Br, NO.sub.2, CN,
O--(C.sub.1-C.sub.4-alkyl), COO--(C.sub.1-C.sub.4-alkyl),
S--COO(C.sub.1-C.sub.4-alkyl), N-[(C.sub.1-C.sub.4)-alkyl].sub.2 or
(C.sub.1-C.sub.6)-alkyl; n is 0, 1 or 2; m is 1; o is 0 or 1; Het
is a heterocyclic 4- to 7-membered ring selected from triazolyl,
tetrazolyl, oxadiazolyl, pyrazolyl, benzimidazolyl, furyl,
triazinyl or 14wherein said heterocyclic 4- to 7-membered ring is
optionally substituted by R7, R8 and R9; and R7, R8, and R9 are
each independently H, F, Cl, Br, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl,
O--(C.sub.2-C.sub.6)-alkynyl, OH, oxo, O--(C.sub.1-C.sub.6)-alkyl,
NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N-[(C.sub.1-C.sub.6)-alkyl].sub.2, COOH,
CO--(C.sub.1-C.sub.6)-alkyl, COO--(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.0-C.sub.6)-alkylene-aryl or
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl, wherein
said (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl, O--(C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.1-C.sub.6)-alkyl, N H--(C.sub.1-C.sub.6)-alkyl,
N-[(C.sub.1-C.sub.6)-alkyl].sub.2, CO--(C.sub.1-C.sub.6)-alkyl,
COO--(C.sub.1-C.sub.6)-alkyl, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.0-C.sub.6)-alkylene-aryl and
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl are
optionally substituted by COOH, CONH.sub.2,
CONH--(C.sub.1-C.sub.6)-alkyl, CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
OCO--(C.sub.1-C.sub.6)-alkyl, F, Cl, (C.sub.1-C.sub.6)-alkyl or
O--(C.sub.1-C.sub.6)-alkyl; and two radicals selected from said R7,
R8 and R9 may optionally be bonded together to form a ring fused
onto said heterocyclic 4- to 7-membered ring; and pharmaceutically
acceptable salts thereof.
3. The compound of claim 2 wherein R1 and R2 are H; R3 and R4 are
each independently F, Cl or Br; R5 is H, F, Cl, Br, OH, NO.sub.2,
CN, (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.4)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, (C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl or
(C.sub.2-C.sub.6)-alkynyl, wherein said (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.4)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1- -C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl and
(C.sub.2-C.sub.6)-alkynyl are optionally mono- or polysubstituted
by F, Cl or Br; A is H, F, Cl, Br, (C.sub.1-C.sub.6)-alkyl,
CF.sub.3, OCF.sub.3, NO.sub.2, CN, O--(C.sub.1-C.sub.6)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, (C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1- -C.sub.6)-alkyl or
SO.sub.2--(C.sub.1-C.sub.6)-alkyl; n is 0, 1 or 2; m is 1; o is 0
or 1; Het is a heterocyclic 4- to 7-membered ring group selected
from triazolyl, tetrazolyl, oxadiazolyl, furyl, triazinyl or
15wherein said 4- to 7-membered heterocyclic ring is optionally
substituted by R7, R8 and R9; and R7, R8, and R9 are each
independently H, (C.sub.1-C.sub.6)-alkyl, OH, oxo, NH.sub.2, COOH,
COO--(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH--(C.sub.1-C.sub.6)-alkyl or
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2, wherein said
(C.sub.1-C.sub.6)-alkyl, COO--(C.sub.1-C.sub.6)-alkyl,
CONH--(C.sub.1-C.sub.6)-alkyl and
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2 are optionally substituted by
COOH; and pharmaceutically acceptable salts thereof.
4. The compound of claim 1 wherein the compound has the structure
Ia 16wherein R5 is H, F, Cl, Br, (C.sub.1-C.sub.6)-alkyl, CF.sub.3,
OCF.sub.3, NO.sub.2, CN, O--(C.sub.1-C.sub.6)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, (C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl or
SO.sub.2--(C.sub.1-C.sub.6)-alkyl; A is H, F, Cl, Br,
(C.sub.1-C.sub.6)-alkyl, CF.sub.3, OCF.sub.3, NO.sub.2, CN,
O--(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1- -C.sub.6)-alkyl or
SO.sub.2--(C.sub.1-C.sub.6)-alkyl; R7 is H,
(C.sub.1-C.sub.6)-alkyl, (C.sub.0-C.sub.6)-alkylene-aryl,
O--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl or
O--(C.sub.2-C.sub.6)-alkynyl, wherein said (C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-aryl, O--(C.sub.1-C.sub.6)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl and O--(C.sub.2-C.sub.6)-alkynyl are
optionally mono- or polysubstituted by F, Cl or Br; R8 is
--(C.dbd.O)--X; X is OH, O--(C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH--(C.sub.1-C.sub.6)-alky- l or N-((C.sub.1-C.sub.6)-alkyl).sub.2;
m is 1 or 2; and n is 1 or 2; and pharmaceutically acceptable salts
thereof.
5. The compound of claim 1 wherein the compound has the structure
Iaa 17wherein R5 is H or F; A is H, F, Cl, (C.sub.1-C.sub.6)-alkyl,
CF.sub.3, COO--(C.sub.1-C.sub.6)-alkyl, COOH or
SO.sub.2--(C.sub.1-C.sub.6)-alkyl; R7 is H or phenyl; R8 is
--(C.dbd.O)--X; and X is OH, O--(C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl or N-[(C.sub.1-C.sub.6)-alkyl].sub.2;
and pharmaceutically acceptable salts thereof.
6. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and one or more compounds of claim 1.
7. A pharmaceutical composition comprising one or more compounds of
claim 1 and at least one further active ingredient.
8. The pharmaceutical composition of claim 7, wherein said further
active ingredient is selected from the group consisting of:
antidiabetics, hypoglycemic active ingredients, HMG-CoA reductase
inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists,
PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP
inhibitors, bile acid absorption inhibitors, CETP inhibitors,
polymeric bile acid adsorbents, LDL receptor inducers, ACAT
inhibitors, antioxidants, lipoprotein lipase inhibitors,
ATP-citrate-lyase inhibitors, squalene synthetase inhibitors,
lipoprotein(a) antagonists, lipase inhibitors, insulins,
sulfonylureas, biguanides, meglitinides, thiazolidinediones,
.alpha.-glucosidase inhibitors, active ingredients acting on the
ATP-dependent potassium channel of the beta cells, CART agonists,
NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF
agonists, CRF agonists, CRF BP antagonists, urocortin agonists,
.beta.3 agonists, MSH (melanocyte-stimulating hormone) agonists,
CCK agonists, serotonin reuptake inhibitors, mixed serotoninergic
and noradrenergic compounds, 5HT agonists, bombesin agonists,
galanin antagonists, growth hormones, growth hormone-releasing
compounds, TRH agonists, uncoupling protein 2 or 3 modulators,
leptin agonists, DA agonists (bromocriptine, Doprexin),
lipase/amylase inhibitors, PPAR modulators, RXR modulators or
TR-.beta. agonists or amphetamines.
9. A method of reducing blood sugar comprising administering to a
patient in need thereof a therapeutically effective amount of a
compound of claim 1.
10. A method for treating lipid and carbohydrate metabolism
disorders comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of claim 1.
11. A method for treating type 2 diabetes comprising administering
to a patient in need thereof a therapeutically effective amount of
a compound of claim 1.
12. A method for treating arteriosclerotic symptoms comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1.
13. A method for treating insulin resistance comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1.
14. A process for preparing a compound of claim 1, which comprises
reacting a urea of formula 2 with a compound of formula 4 18wherein
R1 and R2 are each independently H, O--(C.sub.1-C.sub.6)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, COO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-COO H,
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.- 1-C.sub.6)-alkyl or
(C.sub.1-C.sub.6)-alkyl, wherein said (C.sub.1-C.sub.6)-alkyl is
optionally substituted by OH, O--(C.sub.1-C.sub.4)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.4)-alkyl or N[(C.sub.1-C.sub.6)-alkyl].sub.2; R3
and R4 are each independently F, Cl, Br, OH, NO.sub.2, CN,
(C.sub.1-C.sub.6)-alkyl, 0-(C.sub.1-C.sub.4)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl or (C.sub.2-C.sub.6)-alkynyl, wherein
said (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-Q.sub.4)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl and (C.sub.2-C.sub.6)-alkynyl are
optionally mono- or polysubstituted by F, Cl or Br; R5 is H, F, Cl,
Br, OH, NO.sub.2, CN, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.4)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl or
(C.sub.2-C.sub.6)-alkynyl, wherein said (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.4)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1- -C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl and
(C.sub.2-C.sub.6)-alkynyl are optionally mono- or polysubstituted
by F, Cl or Br; A is H, F, Cl, Br, OH, NO.sub.2, CN,
(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-COO(C.sub.1-C- .sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkeny- l,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
S(O).sub.1-2--(C.sub.1-C.sub.6)-alkyl-,
NH--(C.sub.1-C.sub.6)-alkyl, N-[(C.sub.1-C.sub.6)-alkyl].sub.2,
COOH, COO--(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH--(C.sub.1-C.sub.6)-alkyl, CON-[(C.sub.1-C.sub.6)-alkyl].-
sub.2, SO.sub.2NH.sub.2, SO.sub.2NH--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N-[(C.sub.1-C.sub.6)-alkyl].sub.2 or NHCOR6, wherein said
(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-COO(C.sub.1-C- .sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkeny- l,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
S(O).sub.1-2--(C.sub.1-C.sub.6)-alkyl-,
NH--(C.sub.1-C.sub.6)-alkyl, N-[(C.sub.1-C.sub.6)-alkyl].sub.2,
COO--(C.sub.1-C.sub.6)-alkyl, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
SO.sub.2NH--(C.sub.1-C.sub.6)-alkyl and
SO.sub.2N-[(C.sub.1-C.sub.6)-alky- l].sub.2 are optionally mono- or
polysubstituted by F, Cl, Br, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, CONH--(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6)-alkyl].sub.2 or OCO--(C.sub.1-C.sub.6)-alkyl;
n is 0, 1, 2 or 3; R7 and R8 are each independently H, F, Cl, Br,
(C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl,
0-(C.sub.2-C.sub.6)-alkenyl, O--(C.sub.2-C.sub.6)-alkynyl, OH, oxo,
O--(C.sub.1-C.sub.6)-alkyl, NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N-[(C.sub.1-C.sub.6)-alkyl].sub.2, COOH,
CO--(C.sub.1-C.sub.6)-alkyl, COO--(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.0-C.sub.6)-alkylene-aryl or
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl, wherein
said (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl, O--(C.sub.2-C.sub.6)-alkynyl,
0-(C.sub.1-C.sub.6)-alkyl, NH--(C.sub.1-C.sub.6)-alkyl,
N-[(C.sub.1-C.sub.6)-alkyl].sub.2, CO--(C.sub.1-C.sub.6)-alkyl,
COO--(C.sub.1-C.sub.6)-alkyl, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.0-C.sub.6)-alkylene-aryl and
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl are
optionally substituted by COOH, CONH.sub.2,
CONH--(C.sub.1-C.sub.6)-alkyl, CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
OCO--(C.sub.1-C.sub.6)-alkyl, F, Cl, (C.sub.1-C.sub.6)-alkyl or
O--(C.sub.1-C.sub.6)-alkyl; and said R7 and R8 may optionally be
bonded together to form a ring fused onto said heterocyclic 4- to
7-membered ring; and Y is Cl or 19
15. A process for preparing a compound of claim 1, which comprises
reacting an aniline derivative of formula 3 with a compound of
formula 4 20wherein R2 is H, O--(C.sub.1-C.sub.6)-alkyl,
CO--(C.sub.1-C.sub.6)-alky- l, COO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl or
(C.sub.1-C.sub.6)-alkyl, wherein said (C.sub.1-C.sub.6)-alkyl is
optionally substituted by OH, O--(C.sub.1-C.sub.4)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.4)-alkyl or N[(C.sub.1-C.sub.6)-alkyl].sub.2; R3
and R4 are each independently F, Cl, Br, OH, NO.sub.2, CN,
(C.sub.1-C.sub.6)-alkyl, 0-(C.sub.1-C.sub.4)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl or (C.sub.2-C.sub.6)-alkynyl, wherein
said (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.4)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl and (C.sub.2-C.sub.6)-alkynyl are
optionally mono- or polysubstituted by F, Cl or Br; R5 is H, F, Cl,
Br, OH, NO.sub.2, CN, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.4)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl or
(C.sub.2-C.sub.6)-alkynyl, wherein said (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.4)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1- -C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl and
(C.sub.2-C.sub.6)-alkynyl are optionally mono- or polysubstituted
by F, Cl or Br; A is H, F, Cl, Br, OH, NO.sub.2, CN,
(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-COO(C.sub.1-C- .sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkeny- l,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
S(O).sub.1-2--(C.sub.1-C.sub.6)-alkyl-,
NH--(C.sub.1-C.sub.6)-alkyl, N-[(C.sub.1-C.sub.6)-alkyl].sub.2,
COOH, COO--(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH--(C.sub.1-C.sub.6)-alkyl, CON-[(C.sub.1-C.sub.6)-alkyl].-
sub.2, SO.sub.2NH.sub.2, SO.sub.2NH--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N-[(C.sub.1-C.sub.6)-alkyl].sub.2 or NHCOR6, wherein said
(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-COO(C.sub.1-C- .sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkeny- l,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
S(O).sub.1-2--(C.sub.1-C.sub.6)-alkyl-,
NH--(C.sub.1-C.sub.6)-alkyl, N-[(C.sub.1-C.sub.6)-alkyl].sub.2,
COO--(C.sub.1-C.sub.6)-alkyl, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
SO.sub.2NH--(C.sub.1-C.sub.6)-alkyl and
SO.sub.2N-[(C.sub.1-C.sub.6)-alky- l].sub.2 are optionally mono- or
polysubstituted by F, Cl, Br, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, CONH--(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6)-alkyl].sub.2 or OCO--(C.sub.1-C.sub.6)-alkyl;
n is 0, 1, 2 or 3; R7 and R8 are each independently H, F, Cl, Br,
(C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl,
0-(C.sub.2-C.sub.6)-alkenyl, O--(C.sub.2-C.sub.6)-alkynyl, OH, oxo,
O--(C.sub.1-C.sub.6)-alkyl, NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N-[(C.sub.1-C.sub.6)-alkyl].sub.2, COOH,
CO--(C.sub.1-C.sub.6)-alkyl, COO--(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.0-C.sub.6)-alkylene-aryl or
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl, wherein
said (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl, O--(C.sub.2-C.sub.6)-alkynyl,
0-(C.sub.1-C.sub.6)-alkyl, NH--(C.sub.1-C.sub.6)-alkyl,
N-[(C.sub.1-C.sub.6)-alkyl].sub.2, CO--(C.sub.1-C.sub.6)-alkyl,
COO--(C.sub.1-C.sub.6)-alkyl, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.0-C.sub.6)-alkylene-aryl and
(C.sub.1-C.sub.6)-alkylene-COO-(C.sub.1-C.sub.6)-alkyl are
optionally substituted by COOH, CONH.sub.2,
CONH--(C.sub.1-C.sub.6)-alkyl, CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
OCO--(C.sub.1-C.sub.6)-alkyl, F, Cl, (C.sub.1-C.sub.6)-alkyl or
O--(C.sub.1-C.sub.6)-alkyl; and said R7 and R8 may optionally be
bonded together to form a ring fused onto said heterocyclic 4- to
7-membered ring; and Y is --N.dbd.C=O.
Description
[0001] The invention relates to heterocyclically substituted
benzoylureas and also to their physiologically tolerated salts and
physiologically functional derivatives.
[0002] Heterocyclically substituted benzoylureas having pesticidal
action have already been described in the prior art (EP 0 242
322).
[0003] It is an object of the invention to provide compounds which
exert a therapeutically utilizable blood sugar-reducing action.
[0004] The invention therefore relates to compounds of the formula
I, 2
[0005] wherein
[0006] R1 and R2 are each independently H,
O--(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
COO--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1- -C.sub.6)-alkyl or
(C.sub.1-C.sub.6)-alkyl, wherein said (C.sub.1-C.sub.6)-alkyl may
be substituted by OH, O--(C.sub.1-C.sub.4)-al- kyl, NH.sub.2,
NH(C.sub.1-C.sub.4)-alkyl or N[(C.sub.1-C.sub.6)-alkyl].sub-
.2;
[0007] R3 and R4 are each independently F, Cl, Br, OH, NO.sub.2,
CN, (C.sub.1-C.sub.6)-alkyl, 0-(C.sub.1-C.sub.4)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl or (C.sub.2-C.sub.6)-alkynyl, wherein
said (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.4)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl and (C.sub.2-C.sub.6)-alkynyl are
optionally mono- or polysubstituted by F, Cl or Br;
[0008] R5 is H, F, Cl, Br, OH, NO.sub.2, CN,
(C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.4)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, (C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1- -C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl or
(C.sub.2-C.sub.6)-alkynyl, wherein said (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.4)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl and
(C.sub.2-C.sub.6)-alkynyl are optionally mono- or polysubstituted
by F, Cl or Br;
[0009] A is H, F, Cl, Br, OH, NO.sub.2, CN,
(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-COO(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
S(O).sub.1-2--(C.sub.1-C.sub.6)-alkyl-,
NH--(C.sub.1-C.sub.6)-alkyl, N-[(C.sub.1-C.sub.6)-alkyl].sub.2,
COOH, COO--(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH--(C.sub.1-C.sub.6)-alkyl, CON-[(C.sub.1-C.sub.6)-alkyl].-
sub.2, SO.sub.2NH.sub.2, SO.sub.2NH--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N-[(C.sub.1-C.sub.6)-alkyl].sub.2 or NHCOR6, wherein said
(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-COO(C.sub.1-C- .sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkeny- l,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
S(O).sub.1-2--(C.sub.1-C.sub.6)-alkyl-,
NH--(C.sub.1-C.sub.6)-alkyl, N-[(C.sub.1-C.sub.6)-alkyl].sub.2,
COO--(C.sub.1-C.sub.6)-alkyl, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
SO.sub.2NH--(C.sub.1-C.sub.6)-alkyl and
SO.sub.2N-[(C.sub.1-C.sub.6)-alky- l].sub.2 are optionally mono- or
polysubstituted by F, Cl, Br, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, CONH--(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6)-alkyl]2 or OCO--(C.sub.1-C.sub.6)-alkyl;
[0010] R6 is H, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkylene,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-CONH.sub.2, (C.sub.6-C.sub.10)-aryl,
(C.sub.1-C.sub.4)-alkylene-(C.sub.6-C.sub.10)-ar- yl, heteroaryl,
(C.sub.1-C.sub.4)-alkylene-heteroaryl or CO-heteroaryl, wherein
said (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkylene,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH and
(C.sub.1-C.sub.6)-alkylene-CONH.sub.2 are optionally mono- or
polysubstituted by F, Cl, Br, O(C.sub.1-C.sub.4-alkyl),
COO--(C.sub.1-C.sub.4-alkyl) or N-[(C.sub.1-C.sub.4)-alkyl].sub.2
and said (C.sub.6-C.sub.10)-aryl,
(C.sub.1-C.sub.4)-alkylene-(C.sub.6-C.sub.10)-aryl, heteroaryl,
(C.sub.1-C.sub.4)-alkylene-heteroaryl and CO-heteroaryl are
optionally mono- or poly substituted by F, Cl, Br, NO.sub.2, CN,
O--(C.sub.1-C.sub.4-alkyl), S--COO(C.sub.1-C.sub.4-alkyl),
COO--(C.sub.1-C.sub.4-alkyl), N-[(C.sub.1-C.sub.4)-alkyl].sub.2 or
(C.sub.1-C.sub.6)-alkyl;
[0011] n is 0, 1, 2 or 3;
[0012] m is 1, 2, 3, 4 or 5;
[0013] o is 0, 1, 2 or 3;
[0014] Het is a heterocyclic 4- to 7-membered ring which may
contain up to four N, O or S heteroatoms and wherein said
heterocyclic 4- to 7-membered ring is optionally substituted by R7,
R8 and R9, with the proviso that said heterocyclic 4- to 7-membered
ring cannot be pyrrole; and
[0015] R7, R8, and R9 are each independently H, F, Cl, Br,
(C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl, O--(C.sub.2-C.sub.6)-alkynyl, OH,
oxo, O--(C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N-[(C.sub.1-C.sub.6)-alkyl].sub.2,
COOH, CO--(C.sub.1-C.sub.6)-alkyl, COO--(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.0-C.sub.6)-alkylene-aryl or
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl, wherein
said (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl, O--(C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.1-C.sub.6)-alkyl, NH--(C.sub.1-C.sub.6)-alkyl,
N-[(C.sub.1-C.sub.6)-alkyl].sub.2, CO--(C.sub.1-C.sub.6)-alkyl,
COO--(C.sub.1-C.sub.6)-alkyl, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.0-C.sub.6)-alkylene-aryl and
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl are
optionally substituted by COOH, CONH.sub.2,
CONH--(C.sub.1-C.sub.6)-alkyl, CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
OCO--(C.sub.1-C.sub.6)-alkyl, F, Cl, (C.sub.1-C.sub.6)-alkyl or
O--(C.sub.1-C.sub.6)-alkyl;
[0016] and two radicals selected from said R7, R8 and R9 may
optionally be bonded together to form a ring fused onto said
heterocyclic 4- to 7-membered ring;
[0017] and pharmaceutically acceptable salts thereof.
[0018] Preference is given to compounds of the formula I where
[0019] R1 and R2 are H;
[0020] R3 and R4 are each independently F, Cl or Br;
[0021] R5 is H, F, Cl, Br, OH, NO.sub.2, CN,
(C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.4)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, (C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1- -C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl or
(C.sub.2-C.sub.6)-alkynyl, wherein said (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.4)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, 0-(C.sub.2-C.sub.6)-alkenyl and
(C.sub.2-C.sub.6)-alkynyl are optionally mono- or polysubstituted
by F, Cl or Br;
[0022] A is H, F, Cl, Br, OH, NO.sub.2, CN,
(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-COO(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
S(O).sub.1-2--(C.sub.1-C.sub.6)-alkyl-,
NH--(C.sub.1-C.sub.6)-alkyl, N-[(C.sub.1-C.sub.6)-alkyl].sub.2,
COOH, COO--(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH--(C.sub.1-C.sub.6)-alkyl, CON-[(C.sub.1-C.sub.6)-alkyl].-
sub.2, SO.sub.2NH.sub.2, SO.sub.2NH--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N-[(C.sub.1-C.sub.6)-alkyl].sub.2 or NHCOR6, wherein said
(C.sub.1-C.sub.6)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-COO(C.sub.1-C- .sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkeny- l,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl,
S(O).sub.1-2--(C.sub.1-C.sub.6)-alkyl-, N
H--(C.sub.1-C.sub.6)-alkyl, N-[(C.sub.1-C.sub.6)-alkyl].sub.2,
COO--(C.sub.1-C.sub.6)-alkyl, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
SO.sub.2NH--(C.sub.1-C.sub.6)-alkyl and
SO.sub.2N-[(C.sub.1-C.sub.6)-alky- l].sub.2 are optionally mono- or
polysubstituted by F, Cl, Br, COOH, COO--(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2 or
OCO--(C.sub.1-C.sub.6)-alkyl;
[0023] R6 is H, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkylene,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.1-C.sub.6)-alkylene-CONH.sub.2, (C.sub.6-C.sub.10)-aryl,
(C.sub.1-C.sub.4)-alkylene-(C.sub.6-C.sub.10)-ar- yl, heteroaryl,
(C.sub.1-C.sub.4)-alkylene-heteroaryl or CO-heteroaryl, wherein
said (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.3-C.sub.7)-- cycloalkyl-(C.sub.1-C.sub.4)-alkylene,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkylene-CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH and
(C.sub.1-C.sub.6)-alkylene-CONH.sub.2 groups are optionally mono-
or polysubstituted by F, Cl, Br, O--(C.sub.1-C.sub.4)-alkyl,
COO--(C.sub.1-C.sub.4-alkyl), or N-[(C.sub.1-C.sub.4)-alkyl].sub.2,
and said (C.sub.6-C.sub.10)-aryl,
(C.sub.1-C.sub.4)-alkylene-(C.sub.6-C.sub.10)-aryl, heteroaryl,
(C.sub.1-C.sub.4)-alkylene-heteroaryl and CO-heteroaryl are
optionally mono- or polysubstituted by F, Cl, Br, NO.sub.2, CN,
O--(C.sub.1-C.sub.4-alkyl), COO--(C.sub.1-C.sub.4-alkyl),
S--COO(C.sub.1-C.sub.4-alkyl), N-[(C.sub.1-C.sub.4)-alkyl].sub.2 or
(C.sub.1-C.sub.6)-alkyl;
[0024] n is 0, 1 or 2;
[0025] m is 1;
[0026] o is 0 or 1;
[0027] Het is a heterocyclic 4- to 7-membered ring selected from
triazolyl, tetrazolyl, oxadiazolyl, pyrazolyl, benzimidazolyl,
furyl, triazinyl or 3
[0028] wherein said heterocyclic 4- to 7-membered ring is
optionally substituted by R7, R8 and R9; and
[0029] R7, R8, and R9 are each independently H, F, Cl, Br,
(C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl, O--(C.sub.2-C.sub.6)-alkynyl, OH,
oxo, O--(C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N-[(C.sub.1-C.sub.6)-alkyl].sub.2,
COOH, CO--(C.sub.1-C.sub.6)-alkyl, COO--(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.0-C.sub.6)-alkylene-aryl or
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl, wherein
said (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl, O--(C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.1-C.sub.6)-alkyl, N H--(C.sub.1-C.sub.6)-alkyl,
N-[(C.sub.1-C.sub.6)-alkyl].sub.2, CO--(C.sub.1-C.sub.6)-alkyl,
COO--(C.sub.1-C.sub.6)-alkyl, CONH--(C.sub.1-C.sub.6)-alkyl,
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.0-C.sub.6)-alkylene-aryl and
(C.sub.1-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl are
optionally substituted by COOH, CONH.sub.2,
CONH--(C.sub.1-C.sub.6)-alkyl, CON-[(C.sub.1-C.sub.6)-alkyl].sub.2,
OCO--(C.sub.1-C.sub.6)-alkyl, F, Cl, (C.sub.1-C.sub.6)-alkyl or
O--(C.sub.1-C.sub.6)-alkyl;
[0030] and two radicals selected from said R7, R8 and R9 may
optionally be bonded together to form a ring fused onto said
heterocyclic 4- to 7-membered ring;
[0031] and pharmaceutically acceptable salts thereof.
[0032] Preference is furthermore given to the compounds of the
formula I where
[0033] R1 and R2 are H;
[0034] R3 and R4 are each independently F, Cl or Br;
[0035] R5 is H, F, Cl, Br, OH, NO.sub.2, CN,
(C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.4)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, (C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1- -C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl or
(C.sub.2-C.sub.6)-alkynyl, wherein said (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.4)-alkyl, CO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, O--(C.sub.2-C.sub.6)-alkenyl and
(C.sub.2-C.sub.6)-alkynyl are optionally mono- or polysubstituted
by F, Cl or Br;
[0036] A is H, F, Cl, Br, (C.sub.1-C.sub.6)-alkyl, CF.sub.3,
OCF.sub.3, NO.sub.2, CN, O--(C.sub.1-C.sub.6)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, (C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1- -C.sub.6)-alkyl or
SO.sub.2--(C.sub.1-C.sub.6)-alkyl;
[0037] n is 0, 1 or 2;
[0038] m is 1;
[0039] o is 0 or 1;
[0040] Het is a heterocyclic 4- to 7-membered ring group selected
from triazolyl, tetrazolyl, oxadiazolyl, furyl, triazinyl or 4
[0041] wherein said 4- to 7-membered heterocyclic ring is
optionally substituted by R7, R8 and R9; and
[0042] R7, R8, and R9 are each independently H,
(C.sub.1-C.sub.6)-alkyl, OH, oxo, NH.sub.2, COOH,
COO--(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONH--(C.sub.1-C.sub.6)-alkyl or
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2, wherein said
(C.sub.1-C.sub.6)-alkyl, COO--(C.sub.1-C.sub.6)-alkyl,
CONH--(C.sub.1-C.sub.6)-alkyl and
CON-[(C.sub.1-C.sub.6)-alkyl].sub.2 are optionally substituted by
COOH;
[0043] and pharmaceutically acceptable salts thereof.
[0044] Very particular preference is given to compounds of the
formula Ia 5
[0045] wherein
[0046] R5 is H, F, Cl, Br, (C.sub.1-C.sub.6)-alkyl, CF.sub.3,
OCF.sub.3, NO.sub.2, CN, O--(C.sub.1-C.sub.6)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, (C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1- -C.sub.6)-alkyl or
SO.sub.2--(C.sub.1-C.sub.6)-alkyl;
[0047] A is H, F, Cl, Br, (C.sub.1-C.sub.6)-alkyl, CF.sub.3,
OCF.sub.3, NO.sub.2, CN, O--(C.sub.1-C.sub.6)-alkyl,
CO--(C.sub.1-C.sub.6)-alkyl, (C.sub.0-C.sub.6)-alkylene-COOH,
(C.sub.0-C.sub.6)-alkylene-COO--(C.sub.1- -C.sub.6)-alkyl or
SO.sub.2--(C.sub.1-C.sub.6)-alkyl;
[0048] R7 is H, (C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-aryl, O--(C.sub.1-C.sub.6)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl or O--(C.sub.2-C.sub.6)-alkynyl,
wherein said (C.sub.1-C.sub.6)-alkyl,
(C.sub.0-C.sub.6)-alkylene-aryl, O--(C.sub.1-C.sub.6)-alkyl,
O--(C.sub.2-C.sub.6)-alkenyl and O--(C.sub.2-C.sub.6)-alkynyl are
optionally mono- or polysubstituted by F, Cl or Br;
[0049] R8 is --(C.dbd.O)--X;
[0050] X is OH, O--(C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl or
N-[(C.sub.1-C.sub.6)-alkyl].sub.2;
[0051] m is 1 or 2; and
[0052] n is 1 or 2;
[0053] and pharmaceutically acceptable salts thereof.
[0054] Very particular preference is furthermore given to compounds
of the formula Iaa, 6
[0055] wherein
[0056] R5 is H or F;
[0057] A is H, F, Cl, (C.sub.1-C.sub.6)-alkyl, CF.sub.3,
COO--(C.sub.1-C.sub.6)-alkyl, COOH or
SO.sub.2--(C.sub.1-C.sub.6)-alkyl;
[0058] R7 is H or phenyl;
[0059] R8 is --(C.dbd.O)--X; and
[0060] X is OH, O--(C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl or
N-[(C.sub.1-C.sub.6)-alkyl].sub.2;
[0061] and pharmaceutically acceptable salts thereof.
[0062] The invention relates to compounds of the formula I, in the
form of their racemates, racemic mixtures and pure enantiomers, and
also to their diastereomers and mixtures thereof.
[0063] The alkyl radicals in the substituents A, R1, R2, R3, R4,
R5, R6, R7, R8 and R9 may be either straight-chain or branched.
[0064] When radicals or substituents can occur more than once in
the compounds of the formula I, they may each independently be
defined as specified and be the same or different.
[0065] As a consequence of their higher water solubility compared
to the starting or basic compounds, pharmaceutically acceptable
salts are particularly suitable for medical applications. These
salts have to have a pharmaceutically acceptable anion or cation.
Suitable pharmaceutically acceptable acid addition salts of the
compounds according to the invention are salts of inorganic acids
such as hydrochloric acid, hydrobromic acid, phosphoric acid,
metaphosphoric acid, nitric acid and sulfuric acid, and also
organic acids, e.g. acetic acid, benzenesulfonic acid, benzoic
acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic
acid, glycolic acid, isethionic acid, lactic acid, lactobionic
acid, maleic acid, malic acid, methanesulfonic acid, succinic acid,
p-toluenesulfonic acid and tartaric acid. Suitable pharmaceutically
acceptable basic salts are ammonium salts, alkali metal salts (such
as sodium and potassium salts), alkaline earth metal salts (such as
magnesium and calcium salts), trometamol
(2-amino-2-hydroxymethyl-1,3-pro- panediol), diethanolamine, lysine
or ethylenediamine.
[0066] Salts having a pharmaceutically unacceptable anion, for
example trifluoroacetate, are likewise encompassed by the scope of
the invention as useful intermediates for the preparation or
purification of pharmaceutically acceptable salts and/or for use in
nontherapeutic, for example in vitro, applications.
[0067] The term "physiologically functional derivative" used herein
refers to any physiologically tolerated derivative of a compound of
the formula I according to the invention, e.g. an ester which is
able, on administration to a mammal, e.g. a human, to (directly or
indirectly) form a compound of the formula I or an active
metabolite thereof.
[0068] The physiologically functional derivatives also include
prodrugs of the compounds according to the invention, for example
as described in H. Okada et al., Chem.
[0069] Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be
metabolized in vivo to a compound according to the invention. These
prodrugs may or may not be active themselves.
[0070] The compounds according to the invention can also exist in
different polymorphous forms, for example as amorphous and
crystalline polymorphous forms. All polymorphous forms of the
compounds according to the invention are encompassed by the scope
of the invention and are a further aspect of the invention.
[0071] As used herein, the following definitions apply:
[0072] "Patient" means a warm blooded animal, such as for example
rat, mice, dogs, cats, guinea pigs, and primates such as
humans.
[0073] "Treat" or "treating" means to alleviate symptoms, eliminate
the causation of the symptoms either on a temporary or permanent
basis, or to prevent or slow the appearance of symptoms of the
named disorder or condition.
[0074] "Therapeutically effective amount" means a quantity of the
compound which is effective in treating the named disorder or
condition.
[0075] "Pharmaceutically acceptable carrier" is a non-toxic
solvent, dispersant, excipient, adjuvant or other material which is
mixed with the active ingredient in order to permit the formation
of a pharmaceutical composition, i.e., a dosage form capable of
administration to the patient. One example of such a carrier is a
pharmaceutically acceptable oil typically used for parenteral
administration.
[0076] "Pharmaceutically acceptable salts" means either an acid
addition salt or a basic addition salt which is compatible with the
treatment of patients for the intended use.
[0077] "Pharmaceutically acceptable acid addition salt" is any
non-toxic organic or inorganic acid addition salt of the base
compounds represented by Formula I or any of its intermediates.
Illustrative inorganic acids which form suitable salts include
hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid
metal salts such as sodium monohydrogen orthophosphate and
potassium hydrogen sulfate. Illustrative organic acids which form
suitable salts include the mono-, di- and tri-carboxylic acids.
Illustrative of such acids are, for example, acetic, glycolic,
lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic,
tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic,
hydroxybenzoic, phenylacetic, cinnamic, salicyclic,
2-phenoxybenzoic, p-toluenesulfonic acid and sulfonic acids such as
methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the
mono- or di-acid salts can be formed, and such salts can exist in
either a hydrated, solvated or substantially anhydrous form. In
general, the acid addition salts of these compounds are more
soluble in water and various hydrophilic organic solvents and which
in comparison to their free base forms, generally demonstrate
higher melting points.
[0078] "Pharmaceutically acceptable basic addition salts" means
non-toxic organic or inorganic basic addition salts of the
compounds of Formula (I) or any of its intermediates. Examples are
alkali metal or alkaline-earth metal hydroxides such as sodium,
potassium, calcium, magnesium or barium hydroxides; ammonia, and
aliphatic, alicyclic, or aromatic organic amines such as
methylamine, trimethylamine and picoline. The selection criteria
for the appropriate salt will be known to one skilled in the
art.
[0079] All references given below to "compound(s) of formula I"
refer to compound(s) of the formula I as described above, and also
to their salts, solvates and physiologically functional derivatives
as described herein.
[0080] An aryl radical refers to a phenyl, naphthyl, biphenyl,
tetrahydronaphthyl, alpha- or beta-tetralone, indanyl or
indan-1-onyl radical.
[0081] The compound(s) of the formula (I) can also be administered
in combination with further active ingredients.
[0082] The amount of a compound of formula I which is required in
order to achieve the desired biological effect is dependent upon a
series of factors, for example the specific compound selected, the
intended use, the mode of administration and the clinical condition
of the patient. The daily dose is generally in the range from 0.3
mg to 100 mg (typically from 3 mg and 50 mg) per day per kilogram
of bodyweight, for example 3-10 mg/kg/day. An intravenous dose may,
for example, be in the range from 0.3 mg to 1.0 mg/kg and may
advantageously be administered as an infusion of from 10 ng to 100
ng per kilogram per minute. Suitable infusion solutions for these
purposes may, for example, contain from 0.1 ng to 10 mg, typically
from 1 ng to 10 mg, per milliliter. Individual doses may contain,
for example, from 1 mg to 10 g of the active ingredient. Ampoules
for injections may therefore contain, for example, from 1 mg to 100
mg, and single dose formulations which can be administered orally,
for example tablets or capsules, may contain, for example, from 1.0
to 1000 mg, typically from 10 to 600 mg. The compounds of formula I
may be used for therapy of the abovementioned conditions as the
compounds themselves, although they are preferably in the form of a
pharmaceutical composition with an acceptable carrier. The carrier
of course has to be acceptable, in the sense that it is compatible
with the other constituents of the composition and is not damaging
to the health of the patient. The support may be a solid or a
liquid or both and is preferably formulated with the compound as a
single dose, for example as a tablet, which may contain from 0.05
to 95% by weight of the active ingredient. Further pharmaceutically
active substances may likewise be present, including further
compounds of formula I. The pharmaceutical compositions according
to the invention may be produced by one of the known pharmaceutical
methods which consist essentially of mixing the ingredients with
pharmacologically acceptable carriers and/or excipients.
[0083] Pharmaceutical compositions according to the invention are
those which are suitable for oral, rectal, topical, peroral (for
example sublingual) and parenteral (for example subcutaneous,
intramuscular, intradermal or intravenous) administration, although
the most suitable mode of administration depends in each individual
case on the nature and severity of the condition to be treated and
on the type of the compound of formula I used in each case. Coated
formulations and coated slow-release formulations are also
encompassed by the scope of the invention. Preference is given to
acid- and gastric fluid-resistant formulations. Suitable gastric
fluid-resistant coatings include cellulose acetate phthalate,
polyvinyl acetate phthalate, hydroxypropylmethylcellul- ose
phthalate and anionic polymers of methacrylic acid and methyl
methacrylate.
[0084] Suitable pharmaceutical compounds for oral administration
may be in the form of separate units, for example capsules,
cachets, lozenges or tablets, each of which contains a certain
amount of the compound of formula I; as powder or granules; as
solution or suspension in an aqueous or nonaqueous liquid; or as an
oil-in-water or water-in-oil emulsion. These compositions may, as
already mentioned, be prepared by any suitable pharmaceutical
method which includes a step in which the active ingredient and the
carrier (which may consist of one or more additional ingredients)
are brought into contact. In general, the compositions are prepared
by uniform and homogeneous mixing of the active ingredient with a
liquid and/or finely divided solid carrier, after which the product
is shaped if necessary. For example, a tablet can be produced by
compressing or shaping a powder or granules of the compound,
optionally with one or more additional ingredients. Compressed
tablets can be prepared by tableting the compound in free-flowing
form, for example a powder or granules, optionally mixed with a
binder, lubricant, inert diluent and/or one (or more)
surfactants/dispersants in a suitable machine. Shaped tablets can
be prepared by shaping the pulverulent compound moistened with an
inert liquid diluent in a suitable machine.
[0085] Pharmaceutical compositions which are suitable for peroral
(sublingual) administration include lozenges which contain the
compound of formula I with a flavoring, customarily sucrose, and
gum arabic or tragacanth, and pastilles which include the compound
in an inert base such as gelatin and glycerol or sucrose and gum
arabic.
[0086] Suitable pharmaceutical compositions for parenteral
administration include preferably sterile aqueous preparations of a
compound of formula I which are preferably isotonic with the blood
of the intended recipient. These preparations are preferably
administered intravenously, although the administration may also be
subcutaneous, intramuscular or intradermal as an injection. These
preparations can preferably be produced by mixing the compound with
water and making the solution obtained sterile and isotonic with
the blood. The injectable compositions according to the invention
generally contain from 0.1 to 5% by weight of the active
compound.
[0087] Suitable pharmaceutical compositions for rectal
administration are preferably in the form of single dose
suppositories. These can be prepared by mixing a compound of
formula I with one or more conventional solid carriers, for example
cocoa butter, and shaping the resulting mixture.
[0088] Suitable pharmaceutical compositions for topical use on the
skin are preferably in the form of an ointment, cream, lotion,
paste, spray, aerosol or oil. Useful carriers include petroleum
jelly, lanolin, polyethylene glycols, alcohols and combinations of
two or more of these substances. The active ingredient is generally
present in a concentration of from 0.1 to 15% by weight of the
composition, preferably from 0.5 to 2%.
[0089] Transdermal administration is also possible. Suitable
pharmaceutical compositions for transdermal applications may be in
the form of single plasters which are suitable for long-term close
contact with the epidermis of the patient. Such plasters
advantageously contain the active ingredient in an optionally
buffered aqueous solution, dissolved and/or dispersed in an
adhesive or dispersed in a polymer. A suitable active ingredient
concentration is from approx. 1% to 35%, preferably from approx. 3
to 15%. A particular means of releasing the active ingredient is by
electrotransport or iontophoresis, as described, for example, in
Pharmaceutical Research, 2(6): 318 (1986).
[0090] Further useful active ingredients for combination products
are as follows: All antidiabetics mentioned in the Rote Liste 2001,
chapter 12. They can be combined with the compounds of the formula
I according to the invention, in particular for synergistic
enhancement of the action. The active ingredient combination can be
administered either by separately administering the active
ingredients to the patient or in the form of combination products
in which a plurality of active ingredients are present in one
pharmaceutical preparation. Most of the active ingredients listed
hereinbelow are disclosed in USP Dictionary of USAN and
International Drug Names, US Pharmacopeia, Rockville 2001.
[0091] Antidiabetics include insulin and insulin derivatives, for
example Lantus.RTM. (see www.lantus.com) or HMR 1964, fast-acting
insulins (see U.S. Pat. No. 6,221,633), GLP-1 derivatives, for
example those disclosed in WO 98/08871 of Novo Nordisk A/S, and
orally active hypoglycemic active ingredients.
[0092] The orally active hypoglycemic active ingredients preferably
include sulfonylureas, biguanidines, meglitinides,
oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors,
glucagon antagonists, GLP-1 agonists, potassium channel openers,
for example those disclosed in WO 97/26265 and WO 99/03861 of Novo
Nordisk A/S, insulin sensitizers, inhibitors of liver enzymes which
are involved in the stimulation of gluconeogenesis and/or
glycogenolysis, modulators of glucose uptake, compounds which alter
lipid metabolism such as antihyperlipidemic active ingredients and
antilipidemic active ingredients, compounds which reduce food
intake, PPAR and PXR agonists and active ingredients which act on
the ATP-dependent potassium channel of the beta cells.
[0093] In one embodiment of the invention, the compounds of the
formula I are administered in combination with an HMG-CoA reductase
inhibitor such as simvastatin, fluvastatin, pravastatin,
lovastatin, atorvastatin, cerivastatin, rosuvastatin.
[0094] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a cholesterol
absorption inhibitor, for example, ezetimibe, tiqueside,
pamaqueside.
[0095] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a PPAR gamma
agonist, for example, rosiglitazone, pioglitazone, JTT-501, GI
262570.
[0096] In another embodiment of the invention, the compounds of the
formula I are administered in combination with PPAR alpha agonist,
for example, GW 9578, GW 7647.
[0097] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a mixed PPAR
alpha/gamma agonist, for example, GW 1536, AVE 8042, AVE 8134, AVE
0847, or as described in PCT/US 11833, PCT/US 11490,
DE10142734.4.
[0098] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a fibrate, for
example, fenofibrate, clofibrate, bezafibrate.
[0099] In another embodiment of the invention, the compounds of the
formula I are administered in combination with an MTP inhibitor,
for example, implitapide, BMS-201038, R-103757.
[0100] In another embodiment of the invention, the compounds of the
formula I are administered in combination with bile acid absorption
inhibitor (see, for example, U.S. Pat. No. 6,245,744 or U.S. Pat.
No. 6,221,897), for example, HMR 1741.
[0101] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a CETP inhibitor,
for example, JTT-705.
[0102] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a polymeric bile
acid adsorbent, for example, cholestyramine, colesevelam.
[0103] In another embodiment of the invention, the compounds of the
formula I are administered in combination with an LDL receptor
inducer (see U.S. Pat. No. 6,342,512), for example, HMR1171,
HMR1586.
[0104] In another embodiment of the invention, the compounds of the
formula I are administered in combination with an ACAT inhibitor,
for example, avasimibe.
[0105] In another embodiment of the invention, the compounds of the
formula I are administered in combination with an antioxidant, for
example, OPC-14117.
[0106] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a lipoprotein lipase
inhibitor, for example, NO-1886.
[0107] In another embodiment of the invention, the compounds of the
formula I are administered in combination with an ATP-citrate lyase
inhibitor, for example, SB-204990.
[0108] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a squalene
synthetase inhibitor, for example, BMS-188494.
[0109] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a lipoprotein(a)
antagonist, for example, CI-1027 or nicotinic acid.
[0110] In another embodiment of the invention, the compounds of the
formula I are administered in combination with a lipase inhibitor,
for example, orlistat.
[0111] In another embodiment of the invention, the compounds of the
formula I are administered in combination with insulin.
[0112] In another embodiment, the compounds of the formula I are
administered in combination with a sulfonylurea, for example,
tolbutamide, glibenclamide, glipizide or glimepiride.
[0113] In another embodiment, the compounds of the formula I are
administered in combination with a biguanide, for example,
metformin.
[0114] In another embodiment, the compounds of the formula I are
administered in combination with a meglitinide, for example,
repaglinide.
[0115] In another embodiment, the compounds of the formula I are
administered in combination with a thiazolidinedione, for example,
troglitazone, ciglitazone, pioglitazone, rosiglitazone or the
compounds disclosed in WO 97/41097 of Dr.
[0116] Reddy's Research Foundation, in particular
5-[[4-[(3,4-dihydro-3-me-
thyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.
[0117] In another embodiment, the compounds of the formula I are
administered in combination with an .alpha.-glucosidase inhibitor,
for example, miglitol or acarbose.
[0118] In another embodiment, the compounds of the formula I are
administered in combination with an active ingredient which acts on
the ATP-dependent potassium channel of the beta cells, for example,
tolbutamide, glibenclamide, glipizide, glimepiride or
repaglinide.
[0119] In another embodiment, the compounds of the formula I are
administered in combination with more than one of the
abovementioned compounds, for example in combination with a
sulfonylurea and metformin, a sulfonylurea and acarbose,
repaglinide and metformin, insulin and a sulfonylurea, insulin and
metformin, insulin and troglitazone, insulin and lovastatin,
etc.
[0120] In a further embodiment, the compounds of the formula I are
administered in combination with CART modulators (see
"Cocaine-amphetamine-regulated transcript influences energy
metabolism, anxiety and gastric emptying in mice" Asakawa, A, et
al., M.:Hormone and Metabolic Research (2001), 33(9), 554-558), NPY
antagonists, e.g. naphthalene-1-sulfonic acid
{4-[(4-aminoquinazolin-2-ylamino)methyl]cyclo- hexylmethyl}amide;
hydrochloride (CGP 71683A)), MC4 agonists (e.g.
1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid
[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-
-5-yl)-1-(4-chlorophenyl)-2-oxo-ethyl]amide; (WO 01/91752)), orexin
antagonists (e.g.
1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylure- a;
hydrochlorides (SB-334867-A)), H3 agonists
(3-cyclohexyl-1-(4,4-dimethy-
l-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic
acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g.
[2-methyl-9-(2,4,6-trimethyl
phenyl)-9H-1,3,9-triazafluoren-4-yl]dipropyl- amine (WO 00/66585)),
CRF BP antagonists (e.g. urocortin), urocortin agonists, .beta.3
agonists (e.g. 1-(4-chloro-3-methanesulfonylmethylpheny-
l)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanol;
hydrochlorides (WO 01/83451)), MSH (melanocyte-stimulating hormone)
agonists, CCK-A agonists (e.g.
{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-
thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid
trifluoroacetic acid salt (WO 99/15525)); serotonin reuptake
inhibitors (e.g. dexfenfluramine), mixed serotoninergic and
noradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g.
1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO
01/09111), bombesin agonists, galanin antagonists, growth hormone
(e.g. human growth hormone), growth hormone-releasing compounds
(6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1-
H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)),
TRH agonists (see, for example, EP 0 462 884), uncoupling protein 2
or 3 modulators, leptin agonists (see, for example, Lee, Daniel W.;
Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia.
Leptin agonists as a potential approach to the treatment of
obesity. Drugs of the Future (2001), 26(9), 873-881), DA agonists
(bromocriptine, Doprexin), lipase/amylase inhibitors (e.g. WO
00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or
TR-.beta. agonists.
[0121] In another embodiment of the invention, the other active
ingredient is leptin, see, for example, "Perspectives in the
therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi,
Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001),
2(10), 1615-1622.
[0122] In another embodiment, the other active ingredient is
dexamphatamine or amphetamine.
[0123] In another embodiment, the other active ingredient is
fenfluramine or dexfenfluramine.
[0124] In another embodiment, the other active ingredient is
sibutramine.
[0125] In another embodiment, the other active ingredient is
orlistat.
[0126] In another embodiment, the other active ingredient is
mazindol or phentermine.
[0127] In yet another embodiment, the compounds of the formula I
are administered in combination with dietary fiber materials,
preferably insoluble dietary fiber materials (see, for example,
Carob/Caromax.RTM. (Zunft H J; et al., Carob pulp preparation for
treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001
September-October), 18(5), 230-6.) Caromax is a carob-containing
product supplied by Nutrinova, Nutrition Specialties & Food
Ingredients GmbH, Industriepark Hochst, 65926 Frankfurt/Main)).
Combination with Caromax.RTM. is possible in one preparation or by
separate administration of compounds of the formula I and
Caromax.RTM.. Caromax.RTM. can also be administered in the form of
foodstuffs, for example, in bakery products or muesli bars.
[0128] It will be appreciated that any suitable combination of the
compounds according to the invention with one or more of the
abovementioned compounds and optionally one or more further
pharmacologically active substances is regarded as being covered by
the scope of protection of the present invention. 78
[0129] The contents of all references cited herein are hereby
incorporated in their entirety by reference.
[0130] The above disclosure generally describes the present
invention. A more complete understanding can be obtained by
reference to the following specific examples which are provided
herein for purposes of illustration only, and are not intended to
limit the scope of the invention. The melting points and
decomposition points (m.p.) measured were not corrected and are
generally dependent upon the heating rate.
EXAMPLE 1
[0131] a) 1-(3-fluoro-4-nitrophenyl)-1H-[1,2,4]triazole
[0132] The mixture consisting of 2.5 g of
3-fluoro-4-nitrophenylhydrazine, 1.2 g of [1,2,3]triazine and 50 ml
of ethanol was heated to reflux with stirring for 6 hours. After
concentrating the reaction mixture under reduced pressure, the
residue was worked up by column chromatography (solvent: 99:1
dichloromethane:methanol; silica gel).
1 Yield: 0.8 g m.p.: 99.9.degree. C.
[0133] b) 1-(4-amino-3-fluorophenyl)-1H-[1,2,4]triazole
[0134] Hydrogen was introduced under atmospheric pressure into the
mixture consisting of 260 mg of
1-(3-fluoro-4-nitrophenyl)-1H-[1,2,4]triazole, 30 mg of Pd/C and 30
ml of tetrahydrofuran until the theoretical amount had been taken
up. After filtering off the catalyst with suction and concentrating
the mixture under reduced pressure, the remaining oily residue was
purified by column chromatography (solvent: 98:2
dichloromethane:methanol; silica gel).
2 Yield: 100 mg m.p.: 93.6.degree. C.
[0135] c)
1-(2-chloro-4,5-difluorobenzoyl)-3-(2-fluoro-4-[1,2,4]triazol-1--
yl phenyl)urea
[0136] The solution of equivalent amounts of
2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the
solution of 75 mg of 1-(4-amino-3-fluorophenyl)-1H-[1,2,4]-triazole
in 4 ml of acetonitrile and the mixture was stirred at room
temperature for 30 minutes. The solid was filtered off with suction
and dried under reduced pressure.
3 Yield: 84 mg m.p.: 195.0.degree. C.
EXAMPLE 2
[0137] a)
3-(3-methoxy-4-nitrophenyl)-5-methyl-4H-[1,2,4]triazole
[0138] The mixture consisting of 590 mg g of
3-methoxy-4-nitrobenzoic hydrazide, 6 ml of pyridine and 210 mg of
thioacetamide was heated to 95.degree. C. for 2 hours. After
cooling, the volatile fractions were removed under reduced pressure
at 40.degree. C. and the residue was subjected to column
chromatography purification (silica gel, solvent: 95:5
dichloromethane:methanol)
4 Yield: 100 mg m.p.: 176.0.degree. C.
[0139] b) 2-methoxy-4-(5-methyl-4H-[1,2,4]triazol-3-yl)phenylamine
was prepared by hydrogenating 100 mg of
3-(3-methoxy-4-nitrophenyl)-5-methyl-- 4H-[1,2,4]triazole in the
presence of Pd/C in THF and used further without further
purification.
5 Yield: 110 mg (crude) m.p.: 76.9.degree. C.
[0140] c)
1-(2-chloro-4-fluorobenzoyl)-3-[2-methoxy-4-(5-methyl-4H-[1,2,4]-
triazol-3-yl)-phenyl]urea
[0141] The solution of equivalent amounts of
2-chloro-4-fluorobenzoyl isocyanate was added dropwise to the
solution of 35 mg of
2-methoxy-4-(5-methyl-4H-[1,2,4]triazol-3-yl)phenylamine in 3 ml of
acetonitrile and the mixture was stirred at room temperature for 30
minutes. The solid was then filtered off with suction, stirred with
t-butyl methyl ether, filtered off with suction and dried under
reduced pressure.
6 Yield: 33 mg m.p.: 269.1.degree. C.
EXAMPLE 3
[0142]
1-(2-chloro-4,5-difluorobenzoyl)-3-[2-methoxy-4-(5-methyl-4H-[1,2,4-
]triazol-3-yl)-phenyl]urea
[0143] The solution of equivalent amounts of
2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the
solution of 30 mg of
2-methoxy-4-(5-methyl-4H-[1,2,4]triazol-3-yl)phenylamine in 3 ml of
acetonitrile and the mixture was stirred at room temperature for 30
minutes. The solid was then filtered off with suction, stirred with
isopropanol and dried under reduced pressure.
7 Yield: 50 mg m.p.: 227.5.degree. C.
EXAMPLE 4
[0144] a) ethyl
[5-(3-methoxy-4-nitrophenyl)-4H-[1,2,4]triazol-3-yl]acetat- e
[0145] 477 mg of malonic acid ethyl ester imidic acid ethyl ester
hydrochloride were added to the solution of 633 mg of
3-methoxy-4-nitrobenzoic hydrazide in 2 ml of N-methylpyrrolidone
and the mixture was heated to 140.degree. C. for 3 hours. After
cooling, the mixture was admixed with 50 ml of water and the
product was extracted with ethyl acetate. After drying and
concentrating the organic phase, it was purified by column
chromatography (silica gel, solvent: 95:5
dichloromethane:methanol).
8 Yield: 220 mg m.p.: oil
[0146] b) ethyl
[5-(4-amino-3-methoxyphenyl)-4H-[1,2,4]triazol-3-yl]acetat- e
[0147] 50 mg of Pd/C were added to the solution of 200 mg of ethyl
[5-(3-methoxy-4-nitrophenyl)-4H-[1,2,4]triazol-3-yl]acetate in 100
ml of ethanol and hydrogen was introduced into the mixture at room
temperature until the theoretical amount had been taken up. The
catalyst was then removed by filtration and the filtrate was
concentrated.
9 Yield: 140 mg m.p.: oil
[0148] c)
[5-(3-methoxy-4-nitrophenyl)-4H-[1,2,4]triazol-3-yl]acetic acid
[0149] The mixture of 140 mg of ethyl
[5-(3-methoxy-4-nitrophenyl)-4H-[1,2- ,4]triazol-3-yl]acetate, 5 ml
of methanol and 1 ml of 1 N sodium hydroxide was stirred at room
temperature for 2 hours. Afterwards, the volatile fractions are
removed on a rotary evaporator, the residue is diluted with 10 ml
of water and adjusted to pH 5 using 1 N hydrochloric acid. The
solid was filtered off with suction after the stirring.
10 Yield: 99 mg m.p.: 135.5.degree. C.
[0150] d)
(5-(4-(3-(2-chloro-4-fluorobenzoyl)ureido)-3-methoxyphenyl)-4H-[-
1,2,4]triazol-3-yl)acetic acid
[0151] The solution of equivalent amounts of
2-chloro-4-fluorobenzoyl isocyanate in acetonitrile was added
dropwise to the solution of 89 mg of
[5-(3-methoxy-4-nitrophenyl)-4H-[1,2,4]triazol-3-yl]acetate in 5 ml
of acetonitrile and the mixture was stirred at room temperature
overnight. The solid formed was then filtered off with suction and
dried under reduced pressure.
11 Yield: 70 mg m.p.: >300.degree. C. (decomp.)
EXAMPLE 5
[0152] a) 2-[3-methyl-5-(2-nitrophenyl)-[1,2,4]triazol-4-yl]benzoic
acid
[0153] The mixture consisting of 1.8 g of 2-nitrobenzoic hydrazide,
1.6 g of 2-methylbenzo[d][1,3]oxazin-4-one and 5 ml of
N-methylpyrrolidone was heated to 80.degree. C. with stirring for 2
hours. After cooling, the mixture was admixed with water to slight
cloudiness and stirred for a further 1 hour, during which time a
solid precipitated out which was filtered off with suction,
recrystallized from ethanol and dried under reduced pressure.
12 Yield: 0.89 g m.p.: 228.7.degree. C.
[0154] b) 2-[3-methyl-5-(4-nitrophenyl)-[1,2,4]triazol-4-yl]benzoic
acid was prepared correspondingly from 4-nitrobenzoic hydrazide and
recrystallized from isopropanol.
13 Yield: 0.6 g m.p.: 275.4.degree. C.
[0155] c) 2-[3-(2-aminophenyl)-5-methyl-[1,2,4]triazol-4-yl]benzoic
acid was prepared by hydrogenating 400 mg of
2-[3-methyl-5-(2-nitrophenyl)-[1,- 2,4]triazol-4-yl]benzoic acid in
the presence of Pd/C in tetrahydrofuran and purified by stirring
with dichloromethane.
14 Yield: 240 mg m.p.: 179.4.degree. C.
[0156] d) 2-[3-(4-aminophenyl)-5-methyl-[1,2,4]triazol-4-yl]benzoic
acid was prepared by hydrogenating 270 mg of
2-[3-methyl-5-(4-nitrophenyl)-[1,- 2,4]triazol-4-yl]benzoic acid in
the presence of Pd/C in tetrahydrofuran and purified by column
chromatography (silica gel, solvent: 95:5
dichloromethane:methanol).
15 Yield: 75 mg m.p.: 207.8.degree. C.
[0157] e)
2-(3-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]phenyl}-5-methyl-
-[1,2,4]triazol-4-yl)benzoic acid
[0158] The solution of equivalent amounts of
2-chloro-4-fluorobenzoyl isocyanate was added dropwise to the
solution of 88 mg of
2-[3-(2-aminophenyl)-5-methyl-[1,2,4]triazol-4-yl]benzoic acid in 3
ml of acetonitrile and the mixture was stirred at room temperature
for 30 minutes. The solid was filtered off with suction and dried
under reduced pressure.
16 Yield: 120 mg m.p.: 194.7.degree. C.
EXAMPLE 6
[0159] a) 4-chloro-3-nitrobenzoic acid amidrazone hydrochloride
[0160] The mixture consisting of 6.8 g of ethyl
4-chloro-3-nitrobenzimidat- e hydrochloride, 100 ml of isopropanol
and 3.75 ml of hydrazine hydrate was stirred at room temperature
for 60 minutes. The precipitate was filtered off with suction and
stirred briefly with 50 ml of isopropanol, filtered off with
suction and dried under reduced pressure.
17 Yield: 3.95 g m.p.: 150.2.degree. C.
[0161] b)
3-(4-chloro-3-nitrophenyl)-5-methyl-4H-[1,2,4]triazole
[0162] The mixture consisting of 322 mg of 4-chloro-3-nitrobenzoic
acid amidrazone hydrochloride, 12 ml of toluene and 0.21 ml of
trimethyl orthoacetate was heated to 110.degree. C. for 60 minutes.
The solvent was removed at 40.degree. C. under reduced pressure and
the residue purified by column chromatography (silica gel; 98:2
dichloromethane:methanol).
18 Yield: 65 mg m.p.: 167.9.degree. C.
[0163] c)
3-(3-amino-4-chlorophenyl)-5-methyl-4H-[1,2,4]triazole
[0164] The mixture consisting of 120 mg of
3-(4-chloro-3-nitrophenyl)-5-me- thyl-4H-[1,2,4]triazole, 30 ml of
ethyl acetate and 644 mg of tin chloride was heated to reflux for 6
hours. After cooling, the mixture was washed with water, and the
organic phase was dried over sodium sulfate and concentrated at
40.degree. C. under reduced pressure.
19 Yield: 90 mg m.p.: resin
[0165] d)
1-(2-chloro-4,5-difluorobenzoyl)-3-[2-chloro-5-(5-methyl-4H-[1,2-
,4]triazol-3-yl)phenyl]urea
[0166] The solution of equivalent amounts of
2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the
solution of 85 mg of
3-(3-amino-4-chlorophenyl)-5-methyl-4H-1,2,4-triazole in 8 ml of
acetonitrile and the mixture was stirred at room temperature for 2
hours. The solid formed is then filtered off with suction and dried
under reduced pressure.
20 Yield: 65 mg m.p.: 227.4.degree. C.
[0167] In a similar manner, the following compounds were
prepared:
[0168] e)
1-(2-chloro-4,5-difluorobenzoyl)-3-[2-chloro-5-(4H-[1,2,4]triazo-
l-3-yl)phenyl]urea)
[0169] m.p.: 294.5.degree. C.
[0170] f)
1-(2-chloro-4,5-difluorobenzoyl)-3-[2-trifluoromethoxy-4-(5-hydr-
oxy-1H-[1,2,4]triazol-3-yl)phenyl]urea
[0171] m.p.: >350.degree. C.
EXAMPLE 7
[0172] a) 2-chloro-4-(1H-tetrazol-5-yl)phenylamine
[0173] The mixture consisting of 1.07 g of
4-amino-3-chlorobenzonitrile, 30 ml of xylene and 1.7 g of
trimethyltin azide was stirred at 135.degree. C. for 8 hours. After
cooling, 25 ml of methanol were added, the mixture was stirred at
room temperature for 30 minutes and the volatile constituents were
removed on a rotary evaporator. On stirring, a solid precipitated
out of the mixture obtained in this way, and was filtered off with
suction and briefly dried under reduced pressure. This solid was
dissolved in 1 N sodium hydroxide solution and filtered, and the
product was precipitated by acidifying with 2N hydrochloric acid,
filtered off with suction and dried under reduced pressure.
21 Yield: 1.24 g m.p.: 183.8.degree. C.
[0174] b) 4-(1H-tetrazol-5-yl)-2-trifluoromethoxyphenylamine was
obtained in a similar manner from 505 mg of
4-amino-3-trifluoromethoxybenzonitrile- .
22 Yield: 360 mg m.p.: 183.0.degree. C.
[0175] c)
1-(2-chloro-4-fluorobenzoyl)-3-[2-chloro-4-(1H-tetrazol-5-yl)phe-
nyl]urea
[0176] The solution of equivalent amounts of
2-chloro-4-fluorobenzoyl isocyanate was added dropwise to the
solution of 100 mg of 2-chloro-4-(1H-tetrazol-5-yl)phenylamine in 3
ml of acetonitrile and the mixture was stirred at 40.degree. C. for
60 minutes. The solid formed was filtered off with suction and
dried under reduced pressure.
23 Yield: 115 mg m.p.: 227.6.degree. C.
[0177] d)
1-(2-chloro-4,5-difluorobenzoyl)-3-[2-chloro-4-(1H-tetrazol-5-yl-
)phenyl)urea
[0178] The solution of equivalent amounts of
2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the
solution of 100 mg of 2-chloro-4-(1H-tetrazol-5-yl)phenylamine in 3
ml of acetonitrile and the mixture was stirred at 40.degree. C. for
60 minutes. The solid formed was filtered off with suction and
dried under reduced pressure.
24 Yield: 86 mg m.p.: >300.degree. C.
[0179] e)
1-(2-chloro-4-fluorobenzoyl)-3-[4-(1H-tetrazol-5-yl)-2-trifluoro-
methoxyphenyl]-urea
[0180] was obtained in a similar manner from 100 mg of
5-(4-amino-3-trifluoromethoxyphenyl)tetrazole.
25 Yield: 56 mg m.p.: 276.degree. C.
[0181] f)
1-(2-chloro-4,5-difluorobenzoyl)-3-[4-(1H-tetrazol-5-yl)-(2-trif-
luoromethoxy-phenyl]urea
[0182] was obtained in a similar manner from 100 mg of
4-(1H-tetrazol-5-yl)-2-trifluoromethoxyphenylamine and
2-chloro-4,5-difluorobenzoyl isocyanate.
26 Yield: 98 mg m.p.: 215.0.degree. C.
EXAMPLE 8
[0183] a) 5-(3-methoxy-4-nitrophenyl)-3H-[1,3,4]oxadiazol-2-one
[0184] 1.2 equivalents of a 20% phosgene solution in toluene were
added dropwise to the solution of 850 mg of
3-methoxy-4-nitrobenzoic hydrazide (m.p.: 158.2.degree. C.,
prepared from methyl 3-methoxy-4-nitrobenzoate and hydrazine
hydrate in isopropanol at 80.degree. C.) in 25 ml of dioxane and
the mixture was stirred at room temperature for 1 hour. After
concentrating, the residue was recrystallized from isopropanol,
filtered off with suction and dried under reduced pressure.
27 Yield: 620 mg m.p.: 223.1.degree. C.
[0185] b) [5-(4-amino-3-methoxyphenyl)-3H[1,3,4]oxadiazol-2-one
[0186] Hydrogen was introduced under atmospheric pressure into the
mixture of 550 mg of
5-(3-methoxy-4-nitrophenyl)-3H-[1,3,4]oxadiazol-2-one, 100 mg of
Pd/C and 50 ml of THF up to the theoretical uptake. Afterwards, the
catalyst was filtered off with suction and the mixture was
concentrated to dryness under reduced pressure.
28 Yield: 500 mg m.p.: 206.3.degree. C.
[0187] c)
1-(2-chloro-4-fluorobenzoyl)-3-[4-(5-hydroxy-[1,3,4]oxadiazol-2--
yl)-2-methoxyphenyl]urea
[0188] The solution of equivalent amounts of
2-chloro-4-fluorobenzoyl isocyanate in acetonitrile was added
dropwise to the solution of 103 mg of
25-(4-amino-3-methoxyphenyl)-3H-[1,3,4]oxadiazol-2-one in 5 ml of
acetonitrile and the mixture was stirred at room temperature
overnight. The solid formed was filtered off with suction and dried
under reduced pressure.
29 Yield: 155 mg m.p.: 280.7.degree. C.
[0189] In a similar manner, the following compounds were
prepared:
[0190] d)
1-(2-chloro-4-fluorobenzoyl)-3-[2-(5-hydroxy-[1,3,4]oxadiazol-2--
yl)phenyl]urea
[0191] m.p.:229.7.degree. C.
[0192] e)
1-(2-chloro-4,5-difluorobenzoyl)-3-[4-(5-hydroxy-[1,3,4]oxadiazo-
l-2-yl)-2-methoxyphenyl]urea
[0193] m.p.: 293.1.degree. C.
[0194] f)
1-(2-chloro-4,5-difluorobenzoyl)-3-[2-(5-hydroxy-[1,3,4]oxadiazo-
l-2-yl)phenyl]urea
[0195] m.p.:222.9.degree. C.
[0196] g)
1-(2-chloro-4-fluorobenzoyl)-3-(2-[1,3,4]oxadiazol-2-ylphenyl)ur-
ea
[0197] m.p.: 204.0.degree. C.
[0198] h)
1-(2-chloro-4,5-difluorobenzoyl)-3-(2-[1,3,4]oxadiazol-2-ylpheny-
l)urea
[0199] m.p.: 199.6.degree. C.
EXAMPLE 9
[0200] a) 3-methoxy-4-nitrophenylhydrazine
[0201] 4.5 ml of hydrazine hydrate were added dropwise to the
solution of 3.2 g of 4-fluoro-2-methoxynitrobenzene in 15 ml of
N-methylpyrolidone and the mixture was stirred for 2 hours, which
initially resulted in gentle heating. The mixture was then diluted
with 50 ml of water and stirred, and a precipitate formed which was
filtered off with suction and dried under reduced pressure.
30 Yield: 3.25 g m.p.: 162.5.degree. C.
[0202] b) methyl N'-(3-methoxy-4-nitrophenyl)hydrazinoformate
[0203] 1.5 ml of methyl chloroformate were slowly added dropwise at
room temperature to the solution of 3.0 g of
3-methoxy-4-nitrophenylhydrazine in 25 ml of dichloromethane and
6.6 ml of pyridine. After 2 hours, the volatile fractions were
removed under reduced pressure on a rotary evaporator, the residue
was taken up in water and, after weakly acidifying with 2N
hydrochloric acid, extracted with ethyl acetate. After drying and
concentrating the ethyl acetate phase, a solid residue remained
which was recrystallized from isopropanol.
31 Yield: 3.07 g m.p.: 143.7.degree. C.
[0204] c)
5-methoxy-3-(3-methoxy-4-nitrophenyl)-3H-[1,3,4]oxadiazol-2-one
[0205] The mixture consisting of 3.05 g of methyl
N'-(3-methoxy-4-nitrophe- nyl)hydrazinoformate, 30 ml of
dichloromethane, 5.2 ml of pyridine and 16.5 ml of a 20% toluenic
phosgene solution was stirred at room temperature for 1 hour. After
concentrating under reduced pressure, the semisolid residue was
stirred with 50 ml of water with the addition of 3 ml of 2N
hydrochloric acid, the solid was filtered off with suction and
dried at RT under reduced pressure.
32 Yield: 2.8 g m.p.: 145.1.degree. C.
[0206] d)
3-(4-amino-3-methoxyphenyl)-5-methoxy-3H-[1,3,4]oxadiazol-2-one
hydrochloride
[0207] Hydrogen was introduced at room temperature into the mixture
consisting of 2.8 g of
5-methoxy-3-(3-methoxy-4-nitrophenyl)-3H-[1,3,4]ox- adiazol-2-one,
250 ml of methanol and 0.3 g of Pd/C until the theoretical amount
had been taken up. The catalyst was then removed by filtration and
the filtrate was concentrated. The residue was taken up in ethyl
acetate, the product was precipitated using methanolic hydrochloric
acid, filtered off with suction and dried under reduced
pressure.
33 Yield: 2.0 g m.p.: 245.9.degree. C.
[0208] e)
1-(2-chloro-4-fluorobenzoyl)-3-(2-methoxy-4-(5-methoxy-2-oxo-3H--
[1,3,4]-oxadiazol-3-yl)phenyl)urea
[0209] The solution of equivalent amounts of
2-chloro-4-fluorobenzoyl isocyanate in acetonitrile was added
dropwise to the solution of 0.39 g of
5-methoxy-3-(4-amino-3-methoxyphenyl)-3H-[1,3,4]oxadiazol-2-one
hydrochloride and 0.2 ml of triethylamine in 5 ml of acetonitrile
and the mixture is stirred at room temperature overnight. The solid
formed was filtered off with suction and dried under reduced
pressure.
34 Yield: 0.16 g m.p.: 211.1.degree. C.
[0210] In a similar manner, the following compound was
prepared:
[0211] f)
1-(2-chloro-4-fluorobenzoyl)-3-(2-methyl-4-(5-methylamino-2-oxo--
3H-[1,3,4]-oxadiazol-3-yl)phenyl)urea
[0212] m.p.: 198.0.degree. C.
[0213] g)
1-(2-chloro-4-fluorobenzoyl)-3-[2-chloro-4-(5-methyl-[1,3,4]oxad-
iazol-2-yl)phenyl]urea
[0214] The mixture of 138 mg of
1-(2-chloro-4-fluorobenzoyl)-3-[2-chloro-4-
-(1H-tetrazol-5-yl)phenyl]urea, 180 mg of acetic anhydride, 260 mg
of pyridine and 3 ml of dioxane was heated to 80.degree. C. for 8
hours. After concentrating on a rotary evaporator under reduced
pressure, the residue was stirred with water/glacial acetic acid,
and the solid formed was filtered off with suction, dissolved in
dichloromethane/methanol (1:1), and the solution was separated by
filtration from the insoluble fraction. After concentrating under
reduced pressure, the residue was stirred with ethanol and the
solid was filtered off with suction.
35 Yield: 11 mg m.p.: 198.2.degree. C.
EXAMPLE 10
[0215] a) 5-(2-nitrophenyl)-[1,3,4]oxadiazol-2-ylamine
[0216] 4 ml of a 5M cyanogen bromide solution in acetonitrile were
added dropwise to the solution of 3.6 g of 2-nitrobenzoic hydrazide
in 20 ml of acetonitrile. This resulted first in a clear solution,
then a solid precipitated out which was filtered off with suction
after continuing to stir for a short time, washed again with
acetonitrile and dried under reduced pressure.
36 Yield: 4.3 g m.p.: 211.2.degree. C.
[0217] b) 5-(2-aminophenyl)-[1,3,4]oxadiazol-2-ylamine
[0218] Hydrogen was introduced at atmospheric pressure into the
solution of 350 mg of 5-(2-nitrophenyl)-[1,3,4]oxadiazol-2-ylamine
until the theoretical amount had been taken up. After filtering off
the catalyst with suction and concentrating the mixture under
reduced pressure, the remaining oily residue was purified by column
chromatography (solvent: 95:5 dichloromethane/methanol; silica
gel).
37 Yield: 200 mg m.p.: 199.0.degree. C.
[0219] c)
1-[2-(5-amino-[1,3,4]oxadiazol-2-yl)phenyl]-3-(2-chloro-4,5-difl-
uorobenzoyl)urea
[0220] The solution of equivalent amounts of
2-chloro-4-fluorobenzoyl isocyanate was added dropwise to the
solution of 70 mg of 5-(2-aminophenyl)-[1,3,4]oxadiazol-2-ylamine
in 2 ml of acetonitrile and the mixture was stirred at room
temperature for 30 minutes. The solid was then filtered off with
suction and dried under reduced pressure.
38 Yield: 95 mg m.p.: 205.8.degree. C.
EXAMPLE 11
[0221] a)
N-[4-(N-hydroxycarbamimidoyl)-2-trifluoromethoxyphenyl]acetamide
[0222] The mixture consisting of 610 mg of
N-(4-cyano-2-trifluoromethoxyph- enyl)-acetamide, 15 ml of
isopropanol, 255 mg of hydroxylamine hydrochloride and 410 mg of
sodium acetate was heated to reflux for 5 hours. After cooling, the
insoluble fraction was filtered off, and the filtrate is
concentrated and taken up in a little isopropanol, the product was
precipitated, filtered off with suction and dried by adding water
until the first cloudiness and subsequent stirring.
39 Yield: 280 mg m.p.: 178.2.degree. C.
[0223] b)
N-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-2-trifluoromethox-
yphenyl]-acetamide
[0224] The mixture consisting of 130 mg of
N-[4-(N-hydroxycarbamimidoyl)-2- -trifluoromethoxyphenyl]acetamide,
2 ml of N-methylpyrrolidone, 0.55 ml of pyridine and 0.049 ml of
ethyl chloroformate was stirred at 80.degree. C. for 5 hours. After
cooling, the mixture was diluted with water and the product was
extracted with 20 ml of ethyl acetate. The organic phase was dried
over sodium sulfate and evaporated at 40.degree. C. under reduced
pressure.
40 Yield: 200 mg m.p.: resin
[0225] c)
3-(4-amino-3-trifluoromethoxyphenyl)-4H-[1,2,4]-oxadiazol-5-one
hydrochloride
[0226] The mixture consisting of 200 mg of
N-[4-(5-oxo-4,5-dihydro-[1,2,4]-
oxadiazol-3-yl)-2-trifluoromethoxyphenyl]acetamide, 10 ml of
methanol and 0.5 ml of a 4M solution of hydrochloric acid in
dioxane was stirred at room temperature for 15 hours. After
concentrating the volatile fractions on a rotary evaporator, a
yellowish oil remains.
41 Yield: 190 mg m.p.: oil
[0227] d)
1-(2-chloro-4,5-difluorobenzoyl)-3-[4-(5-oxo-4,5-dihydro-[1,2,4]-
oxadiazol-3-yl)-2-trifluoromethoxyphenyl]urea
[0228] The solution of equivalent amounts of
2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the
solution of 95 mg of
3-(4-amino-3-trifluoromethoxyphenyl)-4H-[1,2,4]-oxadiazol-5-one
hydrochloride and 0.054 ml of Hunig's base in 4 ml of acetonitrile
and the mixture was stirred at room temperature for 30 minutes. The
solid was then filtered off with suction and dried under reduced
pressure.
42 Yield: 55 mg m.p.: 224.5.degree. C.
[0229] In a similar manner, the following examples were
prepared:
[0230] e)
1-(2-chloro-4-fluorobenzoyl)-3-[4-(5-oxo-4,5-dihydro-[1,2,4]oxad-
iazol-3-yl)-2-trifluoromethoxyphenyl]urea
[0231] m.p. 230.1.degree. C.
[0232] f)
1-(2-chloro-4-fluorobenzoyl)-3-[2-chloro-4-(5-oxo-4,5-dihydro-[1-
,2,4]oxadiazol-3-yl)phenyl]urea
[0233] m.p. 243.6.degree. C.
EXAMPLE 12
[0234] a)
5-methyl-2-(3-methyl-4-nitrophenyl)-1,2-dihydropyrazol-3-one
[0235] The mixture of 500 mg of 3-methyl-4-nitrophenylhydrazine,
0.32 ml of methyl acetoacetate and 20 ml of toluene was heated to
100.degree. C. for 8 hours. After cooling, the reaction mixture was
concentrated under reduced pressure and the residue was stirred in
t-butyl methyl ether. The solid was filtered off with suction and
dried under reduced pressure.
43 Yield: 380 mg m.p.: 179.0.degree. C.
[0236] b)
2-(4-amino-3-methylphenyl)-5-methyl-1,2-dihydropyrazol-3-one
[0237] Hydrogen was introduced under atmospheric pressure into the
mixture of 350 mg of
5-methyl-2-(3-methyl-4-nitrophenyl)-1,2-dihydropyrazol-3-one- , 70
mg of Pd/C and 50 ml of tetrahydrofuran until the theoretical
uptake. Afterwards, the catalyst was filtered off with suction and
the mixture was concentrated to dryness under reduced pressure and
the residue was stirred in t-butyl methyl ether. The solid was
filtered off with suction and dried under reduced pressure.
44 Yield: 280 mg m.p.: 59.3.degree. C.
[0238] c)
1-(2-chloro-4-fluorobenzoyl)-3-[2-methyl-4-(3-methyl-5-oxo-2,5-d-
ihydropyrazol-1-yl)phenyl]urea
[0239] The solution of equivalent amounts of
2-chloro-4-fluorobenzoyl isocyanate in acetonitrile was added
dropwise to the solution of 71 mg of
2-(4-amino-3-methylphenyl)-5-methyl-1,2-dihydropyrazol-3-one in 6
ml of acetonitrile and the mixture was stirred at room temperature
overnight. The solid formed was filtered off with suction and dried
under reduced pressure.
45 Yield: 70 mg m.p.: 225.5.degree. C.
EXAMPLE 13
[0240] a)
1-[2-(1H-benzoimidazol-2-yl)phenyl]-3-(2-chloro-4,5-difluorobenz-
oyl)urea
[0241] The solution of equivalent amounts of
2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the
solution of 142 mg of 2-(1H-benzimidazol-2-yl)phenylamine in 8 ml
of acetonitrile and the mixture was stirred at room temperature for
30 minutes. The solid was then filtered off with suction and dried
under reduced pressure.
46 Yield: 250 mg m.p.: 268.degree. C. (decomp.)
[0242] In a similar manner, the following compounds were
prepared:
[0243] b) 5-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]phenyl}fu
ran-2-carboxylic acid
[0244] m.p. 239.3.degree. C.
[0245] c)
5-{2-[3-(2-chloro-4-fluorobenzoyl)ureido]phenyl}furan-2-carboxyl-
ic acid
[0246] m.p. 236.3.degree. C.
EXAMPLE 14
[0247] a)
3-(4-chloro-3-nitrophenyl)-6-methyl-4H-[1,2,4]triazin-5-one
[0248] The mixture consisting of 322 mg of 4-chloro-3-nitrobenzoic
acid amidrazone hydrochloride, 12 ml of ethanol and 0.18 ml of
ethyl pyruvate was heated to 80.degree. C. for 60 minutes. After
cooling, the precipitate was filtered off with suction, washed with
a little ethanol and dried under reduced pressure at 40.degree.
C.
47 Yield: 115 mg m.p.: 247.1.degree. C.
[0249] b)
3-(4-chloro-3-nitrophenyl)-5,6-dimethyl-[1,2,4]triazines
[0250] This compound was obtained in a similar manner to the above
example starting from 2,3-butanedione.
[0251] m.p.: 167.7.degree. C.
[0252] c)
3-(3-amino-4-chlorophenyl)-6-methyl-4H-[1,2,4]triazin-5-one
[0253] This compound was obtained by reducing
3-(4-chloro-3-nitrophenyl)-6- -methyl-4H-[1,2,4]triazin-5-one with
tin chloride.
[0254] m.p.: 258.1.degree. C.
[0255] d)
2-chloro-5-(5,6-dimethyl-[1,2,4]triazin-3-yl)phenylamine
[0256] This compound was obtained by reducing
3-(4-chloro-3-nitrophenyl)-5- ,6-dimethyl-[1,2,4]triazine with tin
chloride.
[0257] m.p.: 211.8.degree. C.
[0258] e)
1-(2-chloro-4,5-difluorobenzoyl)-3-[2-chloro-5-(6-methyl-5-oxo-4-
,5-dihydro-[1,2,4]triazin-3-yl)phenyl]urea
[0259] The solution of equivalent amounts of
2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the
solution of 60 mg of
3-(3-amino-4-chlorophenyl)-6-methyl-4H-[1,2,4]triazin-5-one in 8 ml
of acetonitrile and the mixture was stirred at room temperature for
30 minutes. The solid was filtered off with suction and dried under
reduced pressure.
48 Yield: 75 mg m.p.: 236.6.degree. C.
[0260] f)
1-(2-chloro-4,5-difluorobenzoyl)-3-[2-chloro-5-(5,6-dimethyl-[1,-
2,4]triazin-3-yl)phenyl]urea
[0261] The solution of equivalent amounts of
2-chloro-4,5-difluorobenzoyl isocyanate was added dropwise to the
solution of 75 mg of
2-chloro-5-(5,6-dimethyl-[1,2,4]triazin-3-yl)phenylamine in 8 ml of
acetonitrile and the mixture was stirred at room temperature for 30
minutes. The solid was filtered off with suction and dried under
reduced pressure.
49 Yield: 105 mg m.p.: 229.2.degree. C.
EXAMPLE 15
[0262] a) 1-(4-fluoro-2-nitrophenyl)piperidine-3-carboxamide
[0263] The mixture consisting of 1.62 g of
2,5-difluoronitrobenzene, 1.9 g of nipecotamide and 10 ml of NMP
was heated with stirring to 80.degree. C. for 2 hours. After the
mixture had been allowed to cool, 30 ml of water were added and the
mixture was stirred at RT for 30 minutes. The precipitated solid
was filtered off with suction and dried under reduced pressure.
50 Yield: 2.8 g m.p.: 142.5.degree. C.
[0264] b) 1-(2-amino-4-fluorophenyl)piperidine-3-carboxamide
hydrochloride
[0265] The solution of 2.67 g of
1-(4-fluoro-2-nitrophenyl)piperidine-3-ca- rboxamide in 100 ml of
THF was admixed with 260 mg of Pd/C. This mixture was hydrogenated
in a shaking vessel at atmospheric pressure until the theoretical
amount of hydrogen had been taken up. The mixture is then acidified
with hydrogen chloride dissolved in ethyl acetate, the solid is
filtered off with suction and washed with methanol, and the
filtrate is concentrated under reduced pressure. The residue is
triturated with tert-butyl methyl ether and the solid is filtered
off with suction and dried under reduced pressure.
51 Yield: 2.45 g m.p. 159.2.degree. C.
[0266] c)
1-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-fluorophenyl}pip-
eridine-3-carboxamide
[0267] The equimolar solution of 2-chloro-4,5-difluorobenzoyl
isocyanate in acetonitrile was added dropwise to the solution of
109 mg of 1-(2-amino-4-fluorophenyl)piperidine-3-carboxamide
hydrochloride in 5 ml of acetonitrile with stirring. The mixture
was stirred at RT for 6 h and the precipitate was filtered off with
suction and dried at RT under reduced pressure.
52 Yield: 150 mg m.p.: 216.0.degree. C.
EXAMPLE 16
[0268] a) 1-(4-fluoro-2-nitrophenyl)piperidine-4-carboxylic
acid
[0269] The mixture consisting of 1.62 g of
2,5-difluoronitrobenzene, 1.9 g of piperidine-4-carboxylic acid and
10 ml of NMP was heated with stirring to 80.degree. C. for 2 hours.
After it had been allowed to cool, 30 ml of water were added and
the mixture was made weakly acidic using 2N hydrochloric acid and
stirred at RT. The precipitated solid was filtered off with suction
and dried under reduced pressure.
53 Yield: 3.4 g m.p.: 143.7.degree. C.
[0270] b) 1-(2-amino-4-fluorophenyl)piperidine-4-carboxylic acid
hydrochloride
[0271] The solution of 804 mg of
1-(4-fluoro-2-nitrophenyl)piperidine-4-ca- rboxylic acid in 40 ml
of ethyl acetate was admixed with 3.8 g of tin(II) chloride and
stirred at RT for 2 hours. 50 ml of water were then added and the
mixture was filtered through a clarifying layer. The ethyl acetate
phase was removed, dried over sodium sulfate and concentrated by
rotary evaporator, leaving a semisolid residue which was subjected
directly to further reaction.
54 Yield: 395 mg m.p.: crude product
[0272] c)
1-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-fluorophenyl}pip-
eridine-4-carboxylic acid
[0273] The equimolar solution of 2-chloro-4,5-difluorobenzoyl
isocyanate in acetonitrile was added dropwise to the solution of 53
mg of 1-(2-amino-4-fluorophenyl)piperidine-4-carboxylic acid
hydrochloride in 3 ml of acetonitrile with stirring. The mixture
was stirred at RT for 6 h and the precipitate was filtered off with
suction and dried at RT under reduced pressure.
55 Yield: 75 mg m.p.: 215.9.degree. C.
EXAMPLE 39
[0274] c)
1-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-fluorophenyl}pip-
eridine-4-carboxylic acid sodium salt
[0275] The solution of 100 mg of
1-{2-[3-(2-chloro-4,5-difluorobenzoyl)ure-
ido]-4-fluoro-phenyl}piperidine-4-carboxylic acid in 8 ml of
isopropanol at 60.degree. C. is admixed with the equimolar amount
of 2N sodium hydroxide solution and, after the addition of 20 ml of
water, cooled slowly with stirring. The precipitated product is
filtered off with suction, washed with isopropanol and water and
dried under reduced pressure.
56 Yield: 85 mg m.p. 160.degree. C. (decomp.)
EXAMPLE 41
[0276] c)
1-{2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-4-chlorophenyl}pip-
eridine-4-carboxylic acid
[0277] The mixture consisting of 90 mg of methyl
1-{2-[3-(2-chloro-4,5-dif-
luoro-benzoyl)ureido]-4-chlorophenyl}piperidine-4-carboxylate
(Ex.15), 9.6 mg of lithium hydroxide, 3 ml of water, 3 ml of
methanol and 3 ml of THF is allowed to stand at room temperature
for 36 hours. The volatile fractions are removed at RT under
reduced pressure and the remainder is adjusted to pH=4 using 2N
hydrochloric acid. The precipitate formed is filtered off with
suction and purified by column chromatography (silica gel, solvent:
methylene chloride:methanol=9:1).
57 Yield: 30 mg m.p.: resin
[0278] The compounds of the formula I can be prepared by reacting
ureas of the formula 2 with reactive acid derivatives (formula 4)
such as, for example, with acid chlorides or with anhydrides.
Alternatively, the compounds of the formula I can be prepared by
reacting aniline derivatives of the formula 3 with aroyl
isocyanates. 9
[0279] wherein R1, R2, R3, R4, R5, R7, R8, A, n and Y are each as
defined above in formula 1. If the compound of formula 4 is an acid
chloride, Y is a chloride atom. If the compound of formula 4 is an
isocyanate, Y is the group --N.dbd.C=O. If the compound of formula
4 is an anhydride, Y is a group of formula: 10
58TABLE I Compounds of the formula I 11 Ex. R1 R2 R3 R4 (R5).sub.o
(A).sub.n (Het).sub.m 1c H H Cl F 5-F 2-fluoro
4-((1,2,4)-triazol-1-yl) 2c H H Cl F H 2-OMe
4-(5-methyl-4H-(1,2,4)-tria- zol-3-yl) 3 H H Cl F 5-F 2-OMe
4-(5-methyl-4H-(1,2,4)-tria- zol-3-yl) 4d H H Cl F H 2-OMe
4-(1,2,4-triazole-3-acetic acid- 5-yl) 5e H H Cl F 5-F --H
2-(5-methyl-4-(2-carboxyphe- nyl)-4H-[1,2,4]-triazol-3-yl) 6d H H
Cl F 5-F 2-chloro 5-(5-methyl-(1,2,4)-tria- zol-3-yl) 6e H H Cl F
5-F 2-chloro 3-(4H-(1,2,4)-triazol-3-yl) 6f H H Cl F 5-F
2-OCF.sub.3 4-(5-hydroxy-1-H-(1,2,4)-tria- zol-3-yl) 7c H H Cl F H
2-chloro 4-(1H-tetrazol-5-yl) 7d H H Cl F 5-F 2-chloro
4-(1H-tetrazol-5-yl) 7e H H Cl F H 2-OCF.sub.3 4-(1H-tetrazol-5-yl)
7f H H Cl F 5-F 2-OCF.sub.3 4-(1H-tetrazoi-5-yl) 8c H H Cl F H
2-OMe 4-(5-hydroxy-(1,3,4)-oxa- dia- zol-2-yl) 8d H H Cl F H --H
2-(5-hydroxy-(1,3,4)-oxadia- zol-2-yl) 8e H H Cl F 5-F 2-OMe
4-(5-hydroxy-(1,3,4)-oxadia- zol-2-yl) 8f H H Cl F 5-F --H
2-(5-hydroxy-(1,3,4)-oxadia- zol-2-yl) 8g H H Cl F H --H
2-(1,3,4-oxadiazol-2-yl) 8h H H Cl F 5-F --H
2-(1,3,4-oxadiazol-2-yl) 9e H H Ci F H 2-OMe
4-(5-methoxy-2-oxo-1,3,4- oxadiazol-3-yl) 9f H H Cl F H 2-Me
4-(5-methylamino-2-oxo-1,3, 4-oxadiazol-3-yl) 9g H H Cl F H
2-chloro 4-(5-methyl-1,3,4-oxadia- zol-2-yl) 10c H H Cl F 5-F --H
2-(5-amino-1,3,4-oxadia- zol-2-yl) 11d H H Cl F 5-F 2-OCF.sub.3
4-(5-oxo-4,5-dihydro-(1,- 2,4)- oxadiazol-3-yl) 11e H H Cl F H
2-OCF.sub.3 4-(5-oxo-4,5-dihydro-(1,2,4)- oxadiazol-3-yl) 11f H H
Cl F H --Cl 4-(5-oxo-4,5-dihydro-(1,2,4)- oxadiazol-3-yl) 12c H H
Cl F H 2-Me 4-(3-methyl-5-oxo-pyrazol-1- yl) 13a H H Cl F 5-F --H
2-(benzimidazoi-2-yl) 13b H H Cl F 5-F --H 2-(5-carboxyfur-2-yl)
13c H H Cl F H --H 2-(5-carboxyfur-2-yl) 14e H H Cl F 5-F 2-chloro
5-(6-methyl-5-oxo-4H-(1,2,4)- triazin-3-yl) 14f H H Cl F 5-F
2-chloro 5-(5,6-dimethyl-(1,2,4)- -tria- zin-3-yl)
[0280]
59TABLE II Compounds of the formula Ia 12 Ex. R5 (A).sub.n R7
(A).sub.n R8 p m.p. 15 F 5-F H H 3-CONH.sub.2 2 216.0 16 F 5-F H H
4-COOH 2 221.7 17 F 5-F H H 3-COOH 2 184.2 18 H 5-F H H 3-COOH 2
205.6 19 H 5-F H H 3-CONH.sub.2 2 205.0 20 H 5-F H H 4-COOH 2 230.7
21 F 5-SO.sub.2Me H H 3-COOH 2 resin 22 H 5-SO.sub.2Me H H 3-COOH 2
resin 23 F 5-CF.sub.3 H H 3-COOH 2 resin 24 H 5-CF.sub.3 H H 3-COOH
2 resin 25 H 4-Me H H 3-COOH 2 188.4 26 F 4-Me H H 3-COOH 2 184.9
27 F 5-Me H H 3-COOH 2 219.4 28 H 5-Me H H 3-COOH 2 228.3 29 F 5-Cl
H H 4-COOMe 2 206.6 30 H 5-Cl H H 4-COOMe 2 211.2 31 F 5-Cl H H
3-COOH 2 203.6 32 H 5-Cl H H 3-COOH 2 215.8 33 F 5-COOMe H H 3-COOH
2 227.3 34 H 5-COOMe H H 3-COOH 2 219.4 35 F 5-F H H 3-COOEt 2 oil
36 H 5-F H H 3-COOEt 2 145.2 37 F 5-F H H 3-CONEt.sub.2 2 oil 38 H
5-F H H 3-CONEt.sub.2 2 178.2 39 F 5-F H H 4-COOMe 2 207.0 40 H 5-F
H H 4-COOMe 2 187.2 41 F 5-COOMe H H 4-COOMe 2 221.1 42 H 5-COOMe H
H 4-COOMe 2 205.3 43 H 5-CF.sub.3 H H 4-COOH 2 219.9 44 F
5-SO.sub.2Me H H 4-COOMe 2 231.5 45 H 5-SO.sub.2Me H H 4-COOMe 2
228.2 46 H 5-CF.sub.3 H H 4-COOH 2 206.3 47 F 5-CF.sub.3 H H
4-COOMe 2 resin 48 F H H H 3-COOH 1 resin 49 H 5-CF.sub.3 H H
4-COOMe 2 resin 50 F 5-COOH H H 3-COOH 2 198.4 51 F 5-F 4-phenyl H
4-COOH 2 241.6 52 F 4-COOH H H 4-COOMe 2 238.6 53 F 4-F H H 4-COONa
2 160.9 54 F H H H 4-COOH 2 221.6 55 F 5-Cl H H 4-COOH 2 resin 56 H
H H H 4-COOH 2 227.4 57 F 5-F H H 4-COOH(tris salt) 2 180.6 58 F
5-CF.sub.3 H H 3-COOEt 2 184.6 59 F 5-F 4-phenyl H 4-COOMe 2 218.2
60 F 5-F 4-phenyl H 4-CONH.sub.2 2 236.4
[0281] The compounds of the formula I are notable for favorable
effects on the lipid and carbohydrate metabolism, and in particular
they reduce the blood sugar level and are suitable for treating
type 2 diabetes, insulin resistance, dyslipidemias and the
metabolic syndrome "syndrome X". The compounds are also suitable
for prophylaxis and treatment of arteriosclerotic symptoms. The
compounds may be used alone or in combination with further blood
sugar-reducing active ingredients.
[0282] The effectiveness of the compounds was tested as
follows:
[0283] Glycogen Phophorylase a Activity Test
[0284] The effect of compounds on the activity of the active form
of glycogen phosphorylase (GPa) was measured in the reverse
direction by monitoring the synthesis of glycogen from glucose
1-phosphate by determining the release of inorganic phosphate. All
reactions were carried out as duplicate determinations in 96-well
microtiter plates (half area plates, Costar No. 3696), and the
change in absorption as a consequence of the formation of the
reaction product was measured at the wavelength specified below in
a Multiskan Ascent Elisa Reader (Lab Systems, Finland).
[0285] In order to measure the GPa enzyme activity in the reverse
direction, the conversion of glucose 1-phosphate to glycogen and
inorganic phosphate was measured by the general method of Engers et
al. (Engers H D, Shechosky S, Madsen N B, Can J Biochem 1970
July;48(7):746-754) with the following modifications: human
glycogen phosphorylase a (for example containing 0.76 mg of
protein/ml (Aventis Pharma Deutschland GmbH), dissolved in buffer
solution E (25 mM .beta.-glycerophosphate, pH 7.0, 1 mM EDTA and 1
mM dithiothreitol) was diluted to a concentration of 10 .mu.g of
protein/ml with buffer T (50 mM Hepes, pH 7.0, 100 mM KCl, 2.5 mM
EDTA, 2.5 mM MgCl.sub.26H.sub.2O) and addition of 5 mg/ml of
glycogen. Test substances were prepared as a 10 mM solution in DMSO
and diluted to 50 .mu.M with buffer solution T. To 10 .mu.l of this
solution were added 10 .mu.l of 37.5 mM glucose dissolved in buffer
solution T and 5 mg/ml of glycogen, and also 10 .mu.l of a solution
of human glycogen phosphorylase a (10 .mu.g of protein/ml) and 20
.mu.l of 2.5 mM glucose 1-phosphate. The base value of the activity
of glycogen phosphorylase a in the absence of test substance was
determined by adding 10 .mu.l of buffer solution T (0.1% DMSO). The
mixture was incubated at room temperature for 40 minutes and the
released inorganic phosphate was determined by means of the general
method of Drueckes et al. (al (Drueckes P, Schinzel R, Palm D, Anal
Biochem 1995 Sep. 1;230(1):173-177) with the following
modifications: 50 .mu.l of a stop solution of 7.3 mM of ammonium
molybdate, 10.9 mM of zinc acetate, 3.6% of ascorbic acid, 0.9% of
SDS are added to 50 .mu.l of the enzyme mixture. After 60 minutes
of incubation at 45.degree. C., the absorption was measured at 820
nm. To determine the background absorption, the stop solution was
added immediately after the addition of the glucose 1-phosphate
solution in a separate reaction. This test was carried out at a
concentration of 10 .mu.M of the test substance, in order to
determine the respective inhibition of glycogen phosphorylase a by
the test substance in vitro.
60TABLE 2 Biological activity Ex. % inhibition at 10 .mu.M 1c 94 2c
94 3 100 4d 90 5e 9 6d 100 6e 100 6f 98 7c 100 7d 100 7e 100 7f 100
8c 96 8d 100 8e 97 8f 99 8g 98 8h 100 9e 20 9f 54 9g 79 10c 100 11d
100 11e 98 11f 98 12c 85 13a 48 13b 100 13c 100 14e 97 14f 100 15c
0.3 16c 0.01 17 0.01 18 0.02 19 1.0 20 0.04 21 0.3 22 1.1 23 0.03
24 0.09 25 0.06 26 0.04 27 0.02 28 0.04 29 0.01 30 0.02 31 0.01 32
0.03 33 1.0 34 3.2 35 0.3 36 0.3 37 3.9 38 4.6 39 0.01 40 4.6 41
0.01 42 0.01 43 0.15 44 0.05 45 0.8 46 0.01 47 0.01 48 0.01 49 0.01
50 0.01
[0286] It can be seen from the table that the compounds of the
formula I inhibit the activity of glycogen phosphorylase a and thus
reduce the blood sugar level.
* * * * *
References